Sascha Gerdes

Adipokines and psoriasis

Abstract:  Adipose tissue is an active endocrine organ contributing to the regulation of multiple metabolic pathways via self‐produced bioactive products called adipokines. These adipokines are key players in the pathogenesis of metabolic syndrome and cardiovascular diseases. Co‐occurrence of obesity and psoriasis could lead to interactions of both diseases in which adipokines, at least in part, are involved and may contribute to associated comorbidities of psoriasis. Until today numerous adipokines have been identified of which the most important ones are discussed in the following within the context of obesity, chronic inflammation and their possible role in the pathogenesis of psoriasis. Adipokines could serve as a missing link in the causal relationship between psoriasis and comorbidities and may provide a biomarker for disease severity, risk of comorbidities and treatment success.

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

Abstract:  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 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.

Smoking and alcohol intake in severely affected patients with psoriasis in Germany.

Background: Smoking and alcohol may contribute as triggering factors for psoriasis and are substantial for managing severely affected psoriasis patients. Objectives: To evaluate the general state of smoking and alcohol intake in a group of hospitalized, severely affected patients with psoriasis in comparison with the general population of Germany. Methods: A retrospective, multicentre study analysing data from 1,203 patients with severe psoriasis was performed. Results: 43.3% of all patients were found to be active smokers (males: 46.6%; females: 39.2%) with a higher likelihood as the control group (odds ratio, OR, 2.08, 95% confidence interval, CI, 1.81–2.39; p < 0.0001). 14.9% of all patients were found to be excessive drinkers (female patients: 5.5%; male patients: 22.3%), more likely than the control group (OR 3.10, 95% CI 2.53–3.80; p < 0.0001); males had an OR of 2.86 (95% CI 2.29–3.56; p < 0.0001) and females an OR of 5.12 (95% CI 3.12–8.39; p < 0.0001). Conclusion: Smoking and alcohol intake are independently associated with severe forms of psoriasis. Disease severity is correlated with smoking in both genders as well as with alcohol intake in female patients.

Comedication related to comorbidities : a study in 1203 hospitalized patients with severe psoriasis

Background  Psoriasis is a common dermatological disorder characterized by an immune‐mediated chronic inflammation which is associated with a variety of other diseases commonly referred to as comorbidities. The treatments for these diseases may interfere with the course and the treatment of psoriasis. Little is known on the general drug intake of patients with psoriasis.

Triptolide in the treatment of psoriasis and other immune‐mediated inflammatory diseases

Apart from cancer chronic (auto)immune-mediated diseases are a major threat for patients and a challenge for physicians. These conditions include classic autoimmune diseases like systemic lupus erythematosus, systemic sclerosis and dermatomyositis and also immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis. Traditional therapies for these conditions include unspecific immunosuppressants including steroids and cyclophosphamide, more specific compounds such as ciclosporin or other drugs which are thought to act as immunomodulators (fumarates and intravenous immunoglobulins). With increasing knowledge about the underlying pathomechanisms of the diseases, targeted biologic therapies mainly consisting of anti-cytokine or anti-cytokine receptor agents have been developed. The latter have led to a substantial improvement of the induction of long term remission but drug costs are high and are not affordable in all countries. In China an extract of the herb Tripterygium wilfordii Hook F. (TwHF) is frequently used to treat autoimmune and/or inflammatory diseases due to its favourable cost-benefit ratio. Triptolide has turned out to be the active substance of TwHF extracts and has been shown to exert potent anti-inflammatory and immunosuppressive effects in vitro and in vivo. There is increasing evidence for an immunomodulatory and partly immunosuppressive mechanism of action of triptolide. Thus, compounds such as triptolide or triptolide derivatives may have the potential to be developed as a new class of drugs for these diseases. In this review we summarize the published knowledge regarding clinical use, pharmacokinetics and the possible mode of action of triptolide in the treatment of inflammatory diseases with a particular focus on psoriasis.

Dimethylfumarate inhibits nuclear binding of nuclear factor κB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein β in activated human T cells

Background  Psoriasis is a chronic inflammatory skin disorder in which T‐cell‐mediated immune responses are thought to play a prominent role. Fumaric acid esters (FAEs) have proved to be an effective systemic treatment for psoriasis. The FAE dimethylfumarate (DMF) strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Additionally, it has been demonstrated that the nuclear translocation of the activated transcription factor nuclear factor κB (NF‐κB) is inhibited in human endothelial cells and fibroblasts activated with tumour necrosis factor‐α. The NF‐κB pathway plays a major role in regulating inflammatory cytokine production as well as in cell differentiation and apoptosis. T‐cell survival is also dependent on the activation of NF‐κB and it has been demonstrated in vitro that DMF is an inducer of apoptosis in human T cells. The influence of FAEs on the expression of nuclear transcription factors in T cells has not yet been investigated.

Ustekinumab in the treatment of palmoplantar pustulosis.

MADAM, Palmoplantar pustulosis (PPP) is a challenging disease for dermatologists for which no therapeutic standard has yet been defined. Acitretin and psoralen plus ultraviolet A (PUVA) are commonly used; however, virtually all the therapies used in plaque psoriasis and numerous experimental treatments have been tried in PPP with varying clinical response. This indicates the need for an efficacious systemic long-term treatment for PPP. Ustekinumab is a fully human IgG1j monoclonal antibody approved for the treatment of moderate to severe plaque psoriasis that inhibits the p40 subunit shared by interleukin (IL)-12 and IL-23. One mode of action is a decrease of IL17Aand IL-17F-producing T-helper 17 cells. As IL-17A and IL-17F have been linked to tissue neutrophil recruitment, ustekinumab might be a therapeutic approach in diseases in

Recommendations for detection of individual risk for comorbidities in patients with psoriasis.

Since the pathogenesis of psoriasis vulgaris is now understood as a T cell mediated systemic auto-immune disease, the awareness for the potential systemic implications of the chronic active inflammation has grown. By evaluation of patient registries and study data, several complexes of comorbidities could be identified in recent years, albeit not all of them being clinically relevant. Comorbidity in this context will be defined as two or more diagnostically distinguished medical conditions existing simultaneously, but without a causal link. Nevertheless, there is some strong indication for pathogenetic link between some specified comorbidities and psoriasis at molecular and immunological level. The need for an interdisciplinary assessment of the potential interrelation is obvious. In order to detect the individual risk for comorbidities in patients with moderate to severe psoriasis and to recommend the course of action, a checklist has been developed at an interdisciplinary level that is reduced to the quintessential points for the use in daily practice.

Combination of adalimumab with traditional systemic antipsoriatic drugs – a report of 39 cases

Background: Monotherapy with TNF‐α inhibitors does not always produce a sufficient response in psoriasis patients. Combinations of TNF‐α antagonists such as adalimumab with systemic antipsoriatic therapies such as methotrexate are not approved for use in psoriasis, and the published data are scarce.

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

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 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.