Psoriasis: Friedrich M

Nast A, Kopp IB, Augustin M, Banditt KB, Boehncke WH, Follmann M, Friedrich M, Huber M, Kahl C, Klaus J, Koza J, Kreiselmaier I, Mohr J, Mrowietz U, Ockenfels HM, Orzechowski HD, Prinz J, Reich K, Rosenbach T, Rosumeck S, Schlaeger M, Schmid-Ott G, Sebastian M, Streit V, Weberschock T, Rzany B, Anonymous00272, Anonymous00273. · Division of Evidence Based Medicine (dEBM), Klinik für Dermatologie, Venerologie und Allergologie, Charité-Universitätsmedizin Berlin, Germany. · J Dtsch Dermatol Ges. · Pubmed #17615051 No free full text.

Abstract: Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1 to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, patient surveys have revealed lack of satisfaction with the efficacy of available treatments and a high rate of non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) initiated a project to develop evidence-based guidelines for the management of psoriasis. These resulting Guidelines focus on induction therapy in cases of mild, moderate, and severe plaquetype psoriasis in adults. The Guidelines include evidence-based evaluation of the efficacy of all currently available therapeutic options in Germany. In addition, they offer detailed information on how best to administer the various treatments and give information on contraindications, adverse drug reactions, and drug interactions as well as estimates of practicability and cost. The Guidelines were developed following the recommendations of the Arbeitsgemeinschaft wissenschaftlicher medizinischer Fachgesellschaften (AWMF). The therapeutic recommendations were developed by an expert group and finalized during interdisciplinary consensus conferences.

Nast A, Kopp I, Augustin M, Banditt KB, Boehncke WH, Follmann M, Friedrich M, Huber M, Kahl C, Klaus J, Koza J, Kreiselmaier I, Mohr J, Mrowietz U, Ockenfels HM, Orzechowski HD, Prinz J, Reich K, Rosenbach T, Rosumeck S, Schlaeger M, Schmid-Ott G, Sebastian M, Streit V, Weberschock T, Rzany B. · Division of Evidence Based Medicine, Klinik für Dermatologie, Venerologie, Allergologie, Charité-Universitätsmedizin Berlin, Schumannstrasse 20/21, Berlin, Germany. · Arch Dermatol Res. · Pubmed #17497162 links to  free full text

Abstract: Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1-S126, 2006; or http://www.psoriasis-leitlinie.de ).

Nast A, Kopp IB, Augustin M, Banditt KB, Boehncke WH, Follmann M, Friedrich M, Huber M, Kahl C, Klaus J, Koza J, Kreiselmaier I, Mohr J, Mrowietz U, Ockenfels HM, Orzechowski HD, Prinz J, Reich K, Rosenbach T, Rosumeck S, Schlaeger M, Schmid-Ott G, Sebastian M, Streit V, Weberschock T, Rzany B, Anonymous00487. · Division of Evidence Based Medicine (dEBM), Klinik für Dermatologie, Venerologie und Allergologie, Charité-Universitätsmedizin Berlin. · J Dtsch Dermatol Ges. · Pubmed #17187649 No free full text.

This publication has no abstract.

Friedrich M, Sterry W, Asadullah K. · Psoriasis Studienzentrum, Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Charité, Schumannstr. 20/21, 10117 Berlin, Germany. · J Dtsch Dermatol Ges. · Pubmed #16285288 No free full text.

Abstract: The current standard systemic therapeutic modalities for psoriasis have many potential side effects. Progress made in the understanding of the pathophysiology of psoriasis as a T-cell-mediated dermatosis provide options for new more precise therapeutic approaches. These immunological therapeutic strategies involve the inhibition/depletion of activated T-lymphocytes, the inhibition of antigen presentation and thus the regulation of T-cell activation, the inhibition of adhesion of inflammatory cells, the inhibition of effects of proinflammatory mediators and the administration of antiinflammatory cytokines. This article summarizes these new systemic therapeutic approaches. Clinical results in the early studies have been mixed. In the next years further results of phase II- and phase Ill-studies may be expected, which should allow better assessment of the potential of those particular approaches. Some of these approaches could lead to the approval of new drugs to treat psoriasis and to enhance or replace already existing therapeutic options. Furthermore results of therapeutic experiments should contribute to a better understanding of the disease. As we learn which mechanisms are more or less important for the disease, we will be better able to plan intervention strategies.

Asadullah K, Sabat R, Friedrich M, Volk HD, Sterry W. · Corporate Research Business Area Dermatology, Schering AG, Berlin, Germany. · Curr Drug Targets Inflamm Allergy. · Pubmed #15180472 No free full text.

Abstract: Interleukin (IL)-10 is a pluripotent cytokine with effects on numerous cell populations, in particular circulating and resident immune cells as well as epithelial cells. With its potent immunoregulatory capacities its main biological function seems to be the limitation and termination of inflammatory responses. Thus its low level expression found in psoriasis may have pathophysiological relevance for this immune disease. Remarkably, induction of IL-10 expression was found by conventional antipsoriatic therapies, supporting the hypothesis that IL-10 may be a key cytokine in psoriasis and that application of this cytokine itself may have therapeutic effects. In first clinical trials in patients with established psoriasis IL-10 showed moderate antipsoriatic effects and was well tolerated. Moreover, long term application in psoriatic patients remission showed that IL-10 therapy decreases the incidence of relapse and prolongs the disease free interval. The immunological effects observed during these clinical studies together with in vitro observations suggests that IL-10 exerts its antipsoriatic activity by effects on different cell populations including antigen presenting cells and T-cells (lasting type 1/ type 2 cytokine balance shift), but not through direct effects on keratinocytes. In conclusion IL-10 seems to have major importance in psoriasis. Further investigations, in particular multicenter, placebo-controlled, double blind trials are required to fully determine whether IL-10 application will become a successful antipsoriatic therapy.

Friedrich M, Philipp S, Sabat R, Asadullah K, Sterry W. · Psoriasis Studienzentrum, Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Charité, Schumannstr. 20/21, 10117 Berlin, Germany. · Z Rheumatol. · Pubmed #14579031 No free full text.

Abstract: With a prevalence of 2-3 percent, psoriasis is one of the most common diseases in dermatology. Most patients can be treated sufficiently with topical emollients, but approximately 20 percent of all patients suffering from psoriasis need photo- and/or systemic therapies. Side effects, contraindications, insufficient clinical responses, and lack of long-term efficacy underline the need for novel and improved antipsoriatic therapies. Several biologics interfering with key steps in the immunopathogenesis of psoriasis bear the potential to meet this need with regard to treating moderate to severe psoriasis. Progress made in the understanding of the pathophysiology of psoriasis as T-cell mediated dermatosis does provide options for new, more precise therapeutic approaches. These immunological therapeutic strategies are targeted at the inhibition of T-cell activation, the depletion of activated T-lymphocytes, the inhibition of adhesion of inflammatory cells, the inhibition of effects of proinflammatory cytokines and the application of antiinflammatory cytokines. This article gives a summary of new biologicals used in the treatment of psoriasis. Clinical results received from first applications are inconclusive. Further results of the studies from phase II and phase III can be expected in the next few years, which should make it possible to achieve better assessments of the potential of these types of treatments. Some of these approaches could lead to the approval of new drugs to treat psoriasis and to enhance or replace already existing therapeutic options.

Asadullah K, Volk HD, Friedrich M, Sterry W. · Corporate Research Business Area Dermatology, Schering AG, D-13342 Berlin, Germany. · Arch Immunol Ther Exp (Warsz). · Pubmed #12546067 No free full text.

Abstract: There is a high medical need for better therapies for psoriasis. Based on new insight into the pathophysiology of this frequent immune disease, a number of novel systemic immunomodulatory therapies are currently in clinical development. These include approaches targeting antigen presentation and costimulation, T cell activation and leukocyte adhesion, action of proinflammatory mediators, and modulating the cytokine balance. Although mainly only preliminary data are available so far, these trials contribute to a further understanding of the disease and will eventually lead to new therapeutic options for psoriasis. Moreover, since psoriasis can be considered as a visible model disease for T cell-mediated disorders characterized by a type 1 cytokine pattern in general, such approaches may have impact for other immune disorders as well. Here we review the rationale and the initial clinical data of these important recent experimental therapies.

Döcke WD, Asadullah K, Belbe G, Ebeling M, Höflich C, Friedrich M, Sterry W, Volk HD. · Institute of Medical Immunology, University Hospital Charité, Berlin Humboldt University, Berlin, Germany. · J Leukoc Biol. · Pubmed #19038787 No free full text.

Abstract: Cytokine and anticytokine treatments represent promising approaches for therapy of immune-mediated diseases. In humans, however, regulatory consequences of interference with the cytokine network are only partially understood. Biomarker analysis in clinical studies may help to overcome this complexity and provide novel information about the in vivo relevance of individual cytokines. We report systemic immunological effects of IL-10 therapy in 10 psoriasis patients during a 7-week treatment period followed by a 7-week observation period. IL-10 was given s.c. at 8 microg/kg/day or 20 microg/kg/3 x/week, and a broad range of immunological biomarkers was analyzed in an extended kinetics (17 time-points) before, during, and after IL-10 therapy. Besides the expected anti-inflammatory effects (e.g., inhibition of LPS-induced cytokine secretion), we found unexpected effects, such as activation of NK cells and an increase in parameters indicating proinflammatory activity (C-reactive protein and soluble IL-2R). Furthermore, cumulative effects (IgE and IgA), loss of effect (IL-1R antagonist and IFN-gamma secretion), or counter-regulation during and rebound after IL-10 therapy (TNF-alpha and IL-12/IL-23 p40) were found. Remarkably, some alterations were retained long after the 7-week treatment period (IL-4 secretion, monocytic CD86, and TGF-beta1). In summary, we found manifold effects of IL-10 far beyond the immediate anti-inflammatory activity considered initially. These findings may explain the rather disappointing clinical effects of IL-10 therapy in exacerbated inflammation but also hint to its role for sustained immunological reshaping. They further exemplify the importance of analyzing an extended kinetics of an entire panel of biomarkers for understanding the effects of therapeutic interference with the cytokine network.

Friedrich M, Bock D, Philipp S, Ludwig N, Sabat R, Wolk K, Schroeter-Maas S, Aydt E, Kang S, Dam TN, Zahlten R, Sterry W, Wolff G. · Department of Dermatology and Allergy, University Hospital Charité, Schumannstr. 20/21, 10117 Berlin, Germany. · Arch Dermatol Res. · Pubmed #16362415 No free full text.

Abstract: The selectin family of vascular cell adhesion molecules is comprised of structurally related carbohydrate binding proteins, which mediate the initial rolling of leukocytes on the activated vascular endothelium. Because this process is one of the crucial events in initiating and maintaining inflammation, selectins are proposed to be an attractive target for the development of new antiinflammatory therapeutics. Here, we demonstrate that the synthetic pan-selectin antagonist bimosiamose is effective in pre-clinical models of psoriasis as well as in psoriatic patients. In vitro bimosiamose proved to be inhibitory to E- or P-selectin dependent lymphocyte adhesion under flow conditions. Using xenogeneic transplantation models, bimosiamose reduced disease severity as well as development of psoriatic plaques in symptomless psoriatic skin. The administration of bimosiamose in patients suffering from psoriasis resulted in a reduction of epidermal thickness and lymphocyte infiltration. The clinical improvement was statistically significant (P=0.02) as analyzed by comparison of psoriasis area and severity index before and after treatment. Assessment of safety parameters showed no abnormal findings. These data suggest that pan-selectin antagonism may be a promising strategy for the treatment of psoriasis and other inflammatory diseases.

Friedrich M, Döcke WD, Klein A, Philipp S, Volk HD, Sterry W, Asadullah K. · Department of Dermatology, University Hospital Charité, Berlin Humboldt University, Berlin, Germany. · J Invest Dermatol. · Pubmed #11918715 links to  free full text

Abstract: The ability of interleukin-10 therapy to reduce the severity of exacerbated psoriasis has been demonstrated recently. Considering the immunobiologic properties of this cytokine we investigated the effects of long-term interleukin-10 application on the immune system and duration of psoriasis remission. We performed a placebo-controlled, double-blind, phase II trial using interleukin-10 in patients with chronic plaque psoriasis in remission. Patients received subcutaneous injections with either interleukin-10 (10 microg per kg body weight; n = 7) or placebo (n = 10) three times per week until relapse or study termination after 4 months. The treatment was well tolerated. In the placebo group almost all patients (90%) showed a relapse during the observation period. In contrast to this, only two of seven patients (28.6%) relapsed in the interleukin-10-treated group. Kaplan-Meier analysis revealed a significantly lower relapse incidence in the interleukin-10 than in the placebo group (p = 0.02). The mean relapse-free interval time was 101.6 +/- 12.6 d in the interleukin-10 group in comparison with 66.4 +/- 10.4 d in the placebo group. Immunologic activity of interleukin-10 application was indicated by an increase in soluble interleukin-2 receptor plasma levels and higher ex vivo interleukin-4 secretion capacities. Remarkably, a significant negative correlation was demonstrated between the interleukin-4 secretion capacity and Psoriasis Area and Severity Index score (r = -0.36, p < 0.01). Our data suggest that interleukin-10 therapy is immunologic effective, decreases the incidence of relapse and prolongs the disease-free interval in psoriasis. Its value should be further determined in larger trials and for the prevention of re-exacerbation of other inflammatory disorders with a similar immunologic profile.

Friedrich M, Sterry W, Klein A, Rückert R, Döcke WD, Asadullah K. · No affiliation provided · Acta Derm Venereol. · Pubmed #11859949 No free full text.

This publication has no abstract.

Asadullah K, Döcke WD, Ebeling M, Friedrich M, Belbe G, Audring H, Volk HD, Sterry W. · Department of Dermatology, University Hospital Charité, Berlin Humboldt University, Germany. · Arch Dermatol. · Pubmed #10052405 No free full text.

Abstract: OBJECTIVE: To determine the safety and clinical effects of interleukin 10 (IL-10) treatment of psoriasis. DESIGN AND METHODS: In an open-label phase 2 trial, 10 patients with psoriasis subcutaneously received recombinant human IL-10 over a 7-week period in a dosage of 8 microg/kg daily (n=5) or 20 microg/kg 3 times per week (n=5). Patients were followed up for an additional 5 weeks. RESULTS: The treatment was well tolerated. Antipsoriatic effects were found in all but 1 patient. A significant decrease of the psoriasis area and severity index by 55.3% +/- 11.5% (mean +/- SEM) was observed (P<.02). The antipsoriatic efficiency was confirmed by histological examination. Heterogeneity in the effectiveness was found among the patients, but seems to be independent of the dosage regimen. However, a tendency to a better response was found in the patients who received 20-microg/kg IL-10 3 times per week. Decreasing response in the delayed-type hypersensitivity reaction against recall antigens indicated immunosuppressive effects. Moderate effects on hematopoietic cells were observed. CONCLUSIONS: Our data suggest that IL-10 therapy for psoriasis is safe and possibly clinically effective. Consequently, its value in psoriasis and similar immune diseases should be further determined. Dose-finding, placebo-controlled, double-blind trials are necessary now.

Lee HH, Song IH, Friedrich M, Gauliard A, Detert J, Röwert J, Audring H, Kary S, Burmester GR, Sterry W, Worm M. · Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, D-10117 Berlin, Germany. · Br J Dermatol. · Pubmed #17300238 No free full text.

Abstract: BACKGROUND: Patients with rheumatic diseases receiving antitumour necrosis factor (TNF)-alpha-based treatment may develop cutaneous reactions. OBJECTIVES: To analyse the new onset or aggravation of skin lesions in patients with a rheumatic disease during treatment with TNF-alpha antagonists. METHODS: We conducted a prospective analysis of 35 of 150 patients with a long history of rheumatic disease, including rheumatoid arthritis, ankylosing spondylitis (Bechterew's disease) and psoriatic arthritis, to test for the development of cutaneous manifestations during anti-TNF-alpha (infliximab, adalimumab or etanercept) treatment. RESULTS: Chronic inflammatory skin diseases such as psoriasis and eczema-like manifestations represented the majority of cases (16 of 35). Cutaneous infections caused by viral, bacterial and fungal agents were also observed in many patients (13 of 35). Skin diseases such as dermatitis herpetiformis, leucocytoclastic vasculitis and alopecia occurred in single cases only. CONCLUSIONS: We observed a broad, diverse clinical spectrum with a majority of chronic inflammatory and infectious skin diseases. However, we did not identify individual risk factors and a discontinuation of the anti-TNF-alpha treatment was not necessary if adequate dermatological treatment was performed. The onset of cutaneous side-effects in anti-TNF-alpha-based treatments should be determined by nationwide registries.

Wolf-Henning B, Friedrich M, Mrowietz U, Reich K, Rosenbach T, Sticherling M, Thaçi D, Anonymous00087. · Zentrum der Dermatologie und Venerologie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main. · J Dtsch Dermatol Ges. · Pubmed #16296152 No free full text.

Abstract: About 20% of all psoriasis patients require photo- and/or systemic therapy because of the severity of their disease. Side effects, contraindications, insufficient clinical responses, and lack of long-term efficacy underline the need for novel and improved anti-psoriatic therapies. In recent years, the technology has been established to generate therapeutic molecules from living cells capable of inhibiting disease-relevant mediators or cell-cell interactions. Several of these so-called biologics interfering with key steps in the immunopathogenesis of psoriasis have the potential to meet this need with regard to treating moderate to severe psoriasis. Here, the Psoriasis Study Group of the Arbeitsgemeinschaft Dermatologische Forschung (ADF) analyses the established anti-psoriatic treatment modalities. With the shortcomings of these options in mind, biologics with an immediate relevance for clinical application in the treatment of psoriasis are discussed. The focus is on their potential medical advantages along with safety aspects. Moreover, legal and economical aspects with an impact on the use of biologics are addressed.

Jung M, Sabat R, Krätzschmar J, Seidel H, Wolk K, Schönbein C, Schütt S, Friedrich M, Döcke WD, Asadullah K, Volk HD, Grütz G. · Institute of Medical Immunology, Charité, Humboldt-University Berlin, Berlin, Germany. · Eur J Immunol. · Pubmed #14768053 No free full text.

Abstract: Interleukin-10 (IL-10), originally identified as an inhibitor of pro-inflammatory cytokine production, exerts multiple immunomodulatory functions. Its ability to inhibit a Th1 response has been used in clinical trials for the treatment of inflammatory diseases including psoriasis. However, little is known about the molecular mechanisms of IL-10 functions. We aimed at identifying possible mediators of in vitro IL-10 treatment in monocytes by gene chip technology using Hu95a Affymetrix mRNA arrays with 12,000 genes. To prove relevance of the identified genes for the clinical situation we compared these in vitro results with genes being regulated by IL-10 in peripheral blood mononuclear cells from psoriatic patients undergoing IL-10 therapy. A high proportion of the 1,600 genes up-regulated and 1,300 genes down-regulated in vitro was found to be similarly regulated in vivo. Some genes, which were previously unknown to be regulated by IL-10, can be assigned to known IL-10 functions like e.g. the increase of pathogen clearance. Other new potentially immunomodulating genes have been identified to be regulated by IL-10, but their impact needs to be experimentally evaluated. We could confirm a recently reported up-regulation of heme oxygenase-1 (HO-1). However, we demonstrate that the anti-inflammatory mechanisms of IL-10 remain functional even when HO-1 is irreversibly inhibited.

Asadullah K, Eskdale J, Wiese A, Gallagher G, Friedrich M, Sterry W. · Department of Dermatology, Medical School Charité, Humboldt University Berlin, Berlin, Germany. · J Invest Dermatol. · Pubmed #11407990 links to  free full text

Abstract: Beneficial effects of interleukin-10 therapy and lower endogenous interleukin-10 formation compared with atopic dermatitis and cutaneous T cell lymphomas indicated that interleukin-10 is a key cytokine in psoriasis. The interleukin-10 promoter is highly polymorphic, with two informative microsatellites, interleukin-10.G and interleukin-10.R. In order to understand whether interleukin-10 itself is a predisposing gene for the psoriasis susceptibility we analyzed interleukin-10 promotor polymorphism in patients. The distribution of interleukin-10.G and interleukin10.R microsatellite alleles did not vary between patients (n = 78) and healthy controls (n = 80). In addition, when the psoriasis patients were stratified according to age of onset (younger than 40 y of age, or age 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the interleukin10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an over-representation of the interleukin10.G13 allele in those patients with familial disease (40.4% vs 19.6%, Chi-square = 7.292, p = 0.007). The positive association of allele interleukin10.G13 with familial psoriasis was especially true when patients with an early onset (< 40 y of age) of the disease were compared with those patients with early onset against a nonfamilial background (39.6% vs 14.5%, Chi-square = 8.959, p = 0.003). Patients with age-of-onset of less than 40 were 4-fold [odds ratio = 3.85 (1.55--9.62)] more likely to have a psoriatic family background if they carried this interleukin10.G13 allele. These data suggest that the interleukin-10 locus contributes to the heritability of psoriasis susceptibility.

Asadullah K, Friedrich M, Hanneken S, Rohrbach C, Audring H, Vergopoulos A, Ebeling M, Döcke WD, Volk HD, Sterry W. · Institute of Medical Immunology and Department of Dermatology, University Hospital Charité, Berlin Humboldt University, Berlin, Germany. · J Invest Dermatol. · Pubmed #11348460 links to  free full text

Abstract: Interleukin-10 is an important anti-inflammatory and immunosuppressive cytokine with major impact on several immune reactions, including regulatory mechanisms in the skin. Recently, we performed a phase II trial in psoriatic patients receiving subcutaneously interleukin-10 over 7 wk. The clinical response suggested that interleukin-10 might represent a novel anti-psoriatic drug. In order to understand better the mode of action and to elucidate the effects of systemic interleukin-10 treatment on the skin immune system, skin punch biopsies from sites different from interleukin-10 injection were analyzed. Biopsies were obtained from the patients before, at the end, and 3 wk after interleukin-10 therapy. The results are reported here. Histologic examination showed a decrease of several parameters reflecting the psoriatic disease activity as acanthosis and extension of the horny layer. Immunohistologic examination demonstrated decreasing numbers of infiltrating T cells, dermal CD1a+ cells, and a diminished proliferation of epidermal cells. Using a novel, quantitative reverse transcriptase-polymerase chain reaction approach a significant shift within the cytokine pattern was found. Interleukin-10 therapy led to a decrease of cutaneous interleukin-8 and interleukin-10 mRNA expression. Whereas no significant changes of interleukin-6, tumor necrosis factor-alpha, and interferon-gamma expression were found, interleukin-4 was strongly upregulated suggesting a shift from a type 1 towards a type 2 cytokine pattern. The changes within the local cytokine pattern seem to be disease-related, as an inverse course was found in a single interleukin-10 nonresponding patient. Our findings demonstrate considerable effects of systemic interleukin-10 application on the skin immune systems, which might contribute to the anti-psoriatic activity of interleukin-10.

Friedrich M, Krammig S, Henze M, Döcke WD, Sterry W, Asadullah K. · Department of Dermatology, University Hospital Charité, Humboldt University, 10098 Berlin, Germany. · Arch Dermatol Res. · Pubmed #11142774 No free full text.

This publication has no abstract.

Seifert M, Sterry W, Effenberger E, Rexin A, Friedrich M, Haeussler-Quade A, Volk HD, Asadullah K. · Department of Medical Immunology, Medical School Charité, Humboldt University Berlin, Germany. · Arch Dermatol Res. · Pubmed #10836609 No free full text.

Abstract: IL-10 is a promising candidate for the treatment of cutaneous disorders. Antipsoriatic efficacy of systemic IL-10 treatment has been already demonstrated. This includes histomorphological changes in the epidermis, suggesting effects on keratinocytes. However, less is known about direct effects of IL-10 on this cell population, although effects are likely since IL-10 receptor expression on keratinocytes has been demonstrated recently. Therefore we analysed the effects of IL-10 on keratinocytes in vitro, using concentrations of human recombinant IL-10 corresponding to those detectable in plasma during therapy. Proliferation, cytokine formation (IL-6, IL-8, IL-1ra), and expression of surface molecules (MHC class I and II, costimulatory molecules CD80 and CD86, CD29, CD54, CD95) were measured in stimulated and unstimulated cells. Although stimulation influenced the expression levels of certain surface markers, no or only slight effects of IL-10 were found. In contrast considerable inhibitory effects of IL-10 on surface molecule expression and cytokine secretion by peripheral blood human monocytes were observed. Our results suggest that the antipsoriatic activity of IL-10 is rather caused by modulatory effects on circulating immune cells, which subsequently might infiltrate the skin, than by direct effects on human keratinocytes. Considering the remarkable antipsoriatic activity of IL-10 and the observation that IL-10 seem to act on peripheral blood mononuclear cells but not on keratinocytes provide further evidence that circulating immune cells play a key role in the pathology of psoriasis. Finally, our results argue against the value of IL-10 therapy in dermatoses strictly limited to keratinocyte involvement.

Asadullah K, Gellrich S, Haeussler-Quade A, Friedrich M, Döcke WD, Jahn S, Sterry W. · Department of Dermatology, Medical School Charité, Humboldt University Berlin, Germany. · Exp Dermatol. · Pubmed #10688378 No free full text.

Abstract: Physiologically, B-lymphocytes are not present in the skin. Even in pathological situations they rarely occur. In contrast, primary cutaneous B-cell lymphomas (CBCL) are characterized by proliferation of B lymphocytes within the skin. This suggests the existence of a certain microenvironment supporting homing and expansion of clonal B cells. Cytokines were demonstrated to be involved in the pathogenesis of cutaneous lymphomas of T-cell origin. Cytokine expression in cutaneous B-cell lymphoma lesions, however, has not been investigated so far. Therefore, the mRNA level of several cytokines was analyzed in biopsies from 7 patients with CBCL and compared to pleomorphic T-cell lymphoma (n = 6), psoriasis (n = 9), and healthy skin (n = 7), using a competitive RT-PCR approach. An overexpression of TNF-alpha, IL-10, and IL-6 was found. Enhanced IL-8 mRNA expression was detected in 2/7 cases. The overexpression of IL-6 and IL-10 in CBCL might be of particular importance, since these cytokines are considered to support B-cell growth. Additionally, the overexpression of IL-10 may contribute to tumor progression since this immunosuppressive cytokine might be involved in downregulation of immunological tumor surveillance, in part by inhibiting type 1 cytokine formation. In fact, we did not detect IFN-gamma and IL-2 expression. Taken together, we found a cytokine pattern in CBCL lesions which might contribute to tumor B-cell growth.