Sandra Boehncke

The 'psoriatic march': a concept of how severe psoriasis may drive cardiovascular comorbidity.

Abstract:  There is increasing awareness that psoriasis is more than ‘skin deep’. Several recent reviews focussed on biomarkers indicating the systemic dimension of psoriasis and the aspect of comorbidity psoriasis shares with other chronic inflammatory diseases, such as Crohn’s disease and rheumatoid arthritis. Of emerging significance is the relationship to cardiovascular disease, as this contributes substantially to the patients’ increased mortality. In this viewpoint, we examine currently available evidence favouring the concept of a causal link between psoriasis and cardiovascular disease: systemic inflammation may cause insulin resistance, which in turn triggers endothelial cell dysfunction, leading to atherosclerosis and finally myocardial infarction or stroke. While this ‘psoriatic march’ is not yet formally proven, it raises clinically and academically relevant questions, and gains support by recent observations of numerous investigators.

Psoriasis patients show signs of insulin resistance

Background  Recent observations suggest that psoriasis is a risk factor for the development of coronary artery calcification which in turn represents an indicator for atherosclerosis.

Managing comorbid disease in patients with psoriasis

#### Summary points Psoriasis is a common, chronic inflammatory skin disease that typically presents with sharply demarcated, red scaly dermatological plaques that may be painful and stigmatising (fig 1⇓). It causes a high burden of disease, comparable to that of cancer or diabetes mellitus.1 In about a quarter of people with psoriasis the condition is severe enough for them to need ultraviolet light therapy, systemic drug treatment, or hospital admission. Fig 1 Patient with severe psoriasis: red scaly plaques cover more than 10% of the body surface area; this patient also has a body mass index >25 Three recent developments have changed our understanding of psoriasis substantially. Firstly, researchers identified “Th17 cells” (a new type of lymphocyte) as important effector cells in autoimmune diseases.2 Indeed, the first drug that interferes with the functions of Th17 cells was approved in 2009, its first indication being psoriasis.3 Secondly, psoriasis is now confirmed as a systemic disease, as serum biomarkers for inflammation are raised in patients with psoriasis.4 Finally, psoriasis frequently occurs alongside other diseases.5 This review focuses on comorbid …

Effective continuous systemic therapy of severe plaque-type psoriasis is accompanied by amelioration of biomarkers of cardiovascular risk: results of a prospective longitudinal observational study

Background  Severe psoriasis is associated with significant cardiovascular mortality.

Interleukin-1β interferes with epidermal homeostasis through induction of insulin resistance: implications for psoriasis pathogenesis

Response pathways of the metabolic and the immune system have been evolutionary conserved, resulting in a high degree of integrated regulation. Insulin is a central player in the metabolic system and potentially also in the homeostasis of the skin. Psoriasis is a frequent and often severe autoimmune skin disease, clinically characterized by altered epidermal homeostasis, of which the molecular pathomechanisms are only little understood. In this study, we have examined a potential role for insulin signaling in the pathogenesis of this disease. We show that IL-1β is present in high quantities in tissue fluid collected via microdialysis from patients with psoriasis; these levels are reduced under successful anti-psoriatic therapy. Our results suggest that IL-1β contributes to the disease by dual effects. First, it induces insulin resistance through p38MAPK (mitogen-activated protein kinase), which blocks insulin-dependent differentiation of keratinocytes, and at the same time IL-1β drives proliferation of keratinocytes, both being hallmarks of psoriasis. Taken together, our findings point toward insulin resistance as a contributing mechanism to the development of psoriasis; this not only drives cardiovascular comorbidities, but also its cutaneous phenotype. Key cytokines inducing insulin resistance in keratinocytes and kinases mediating their effects may represent attractive targets for novel anti-psoriatic therapies.

Cardiovascular mortality in psoriasis and psoriatic arthritis: epidemiology, pathomechanisms, therapeutic implications, and perspectives.

Psoriasis and psoriatic arthritis are associated with an increased cardiovascular mortality. Although the underlying pathogenesis is not yet fully understood, it is clear that these seemingly organ-specific disorders cause a systemic inflammatory burden as mirrored by elevated biomarkers in the patients’ blood. Emerging evidence points toward insulin resistance and endothelial dysfunction as direct consequences; these in turn drive the process of atherosclerosis. As psoriasis and psoriatic arthritis therefore represent cardiovascular risk factors, they must be taken into account by primary care physicians when defining treatment goals for the comorbidities of the respective patients (e.g., arterial hypertension or dyslipidemia). Secondary and tertiary care physicians need to consider a more comprehensive treatment approach, including aspects of lifestyle intervention. Finally, effective long-term anti-inflammatory, disease-modifying therapy may contribute to reducing patients’ cardiovascular risk.

Anti-inflammatory effects of the GABAB receptor agonist baclofen in allergic contact dermatitis

Please cite this paper as: Anti‐inflammatory effects of the GABAB receptor agonist baclofen in allergic contact dermatitis. Experimental Dermatology 2010; 19: 661–666.

Tolerance to coxibs in patients with intolerance to non-steroidal anti-inflammatory drugs (NSAIDs): a systematic structured review of the literature

Adverse events triggered by non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drug-related intolerance reactions in medicine; they are possibly related to inhibition of cyclooxygenase-1. Coxibs, preferentially inhibiting cyclooxygenase-2, may therefore represent safe alternatives in patients with NSAID intolerance. We reviewed the literature in a systematic and structured manner to identify and evaluate studies on the tolerance of coxibs in patients with NSAID intolerance. We searched MEDLINE (1966–2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966–2006) up to December 9, 2006, and analysed all publications included using a predefined evaluation sheet. Symptoms and severity of adverse events to coxibs were analysed based on all articles comprising such information. Subsequently, the probability for adverse events triggered by coxibs was determined on analyses of double-blind prospective trials only. Among 3,304 patients with NSAID intolerance, 119 adverse events occurred under coxib medication. All adverse events, except two, have been allergic/urticarial in nature; none was lethal, but two were graded as life-threatening (grade 4). The two non-allergic adverse events were described as a grade 1 upper respiratory tract haemorrhage, and a grade 1 gastrointestinal symptom, respectively. In 13 double-blind prospective studies comprising a total of 591 patients with NSAID intolerance, only 13 adverse reactions to coxib provocations were observed. The triggering coxibs were rofecoxib (2/286), celecoxib (6/208), etoricoxib (4/56), and valdecoxib (1/41). This review documents the good tolerability of coxibs in patients with NSAID intolerance, for whom access to this class of drugs for short-term treatment of pain and inflammation is advantageous.

Endogenous μ-opioid peptides modulate immune response towards malignant melanoma.

Abstract:  Opioids exert major effects not only in the central nervous system but also in immune responses. We investigated the effects of μ‐opioid peptides, secreted by tumor cells, on anti‐tumor immune responses. For this purpose, tumor growth was studied in wild‐type and μ‐opioid receptor–deficient (MOR−/−) mice injected with B16 melanoma cells. The ability of these cells to produce opioids was studied by Western blots in vitro. Finally, biopsy material from human melanomas was investigated by immunohistochemistry for ß endorphin expression. Injection of B16 melanoma cells, producing endogenous ß endorphin, in the flank of MOR−/− mice revealed a profound reduction in tumor growth, paralleled by a significantly higher infiltration of immune cells into the tumors, when compared to tumor growth after injection of B16 melanoma cells into wild‐type mice. Opioids present in B16 cell supernatant significantly reduced the proliferation of normal but not MOR−/− leucocytes. Immunohistochemical analyses of biopsies from human melanoma tissues showed a positive correlation between expression of ß endorphin and tumor progression. Our data provide evidence that μ‐opioid peptides may play a major role in cancer progression by modulating immune response. This finding may have implications for the future optimization of immunointerventions for cancer.

Microdialysis documents changes in the micromilieu of psoriatic plaques under continuous systemic therapy

Abstract:  Microdialysis is a novel technique suitable to analyse soluble mediators in the skin compartment. We applied this methodical approach to monitor changes in the micromilieu of psoriatic plaques under therapy. Tissue fluid was collected from lesional and non‐lesional skin of three patients with severe plaque‐type psoriasis prior to as well as after 12 weeks of continuous oral therapy with fumaric acid esters. Concentrations of a spectrum of cytokines and adipokines were measured using a commercial fluorescent bead immunoassay. The procedure was well tolerated even without local anaesthesia. Prior to initiation of therapy, we found elevated levels for IL‐2, IL‐6, IL‐18, IL‐23, and resistin in lesional versus non‐lesional skin, whereas adiponectin levels were higher in non‐lesional skin. All patients showed significant clinical improvement under treatment, paralleled by reduced concentrations of IL‐6, IL‐18, IL‐23, and resistin, but not IL‐2 and adiponectin in lesional skin. Thus, we were able to demonstrate through microdialysis a shift in the micromilieu of psoriatic plaques, characterized by reduced levels of pro‐inflammatory mediators in three patients under effective systemic anti‐inflammatory therapy with fumaric acid esters. Our observations need to be confirmed by larger studies. This approach is limited by practical aspects as it is very time‐consuming, but suitable to directly explore pathomechanisms causing the psoriatic phenotype in general and insulin resistance in the skin compartment in particular.