'Upgrading' psoriasis responsibly.

Psoriasis is a 'pacemaker' in dermatology. Substantial progress has been made regarding our understanding of its pathophysiology and genetic background, fuelling developments in cutaneous biology in general. Besides, the clinical perspective on psoriasis is currently changing, taking into consideration comorbidity and the systemic dimensions of this seemingly organ-specific inflammation. The availability of drugs exhibiting fewer contraindications and improved long-term safety opened a discussion around replacing a relatively limited (regarding both objectives and duration) 'therapeutic' by a much broader 'management' approach when it comes to treating psoriasis as a systemic disease. The question arises whether this 'upgrade' is warranted.

More than skin-deep: the many dimensions of the psoriatic disease.

Psoriasis is among the most common skin diseases, exhibiting a wide spectrum of clinical manifestations. Joint involvement in the form of psoriatic arthritis is readily recognised, but both frequency and severity of this manifestation have long been underestimated. More recently, additional important diseases have been found to be associated with psoriasis, including the metabolic syndrome (or components thereof), cardiovascular diseases, lymphoma, and anxiety/depression. In the past, psoriasis treatment aimed at suppressing acute rashes. Current concepts regard psoriasis as a chronic systemic inflammatory condition and cardiovascular risk factor. In the light of this concept, long-term disease control through systemic maintenance therapy is increasingly recommended by experts. This approach became feasible with the approval of numerous biologics for the treatment of psoriasis. But to really address all medical needs of psoriasis patients, a truly interdisciplinary, comprehensive management approach is needed. Several national societies have already published algorithms to ensure that this need will be implemented in the daily practice of dermatologists and nondermatologists alike.

Diurnal variation of hypothalamic function and chronic subthalamic nucleus stimulation in Parkinson's disease.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves quality of life in patients with advanced Parkinson's disease (PD), but is associated with neuropsychiatric side effects and weight gain in some individuals. The pathomechanisms of these phenomena are still unknown. Considering anatomical and functional connections of the STN with the hypothalamic-pituitary (HP) system, we prospectively investigated whether chronic STN-DBS alters HP functioning in 11 PD patients. METHODS: Basal hormone levels of the HP-adrenal (HPA), HP-gonadal and HP-somatotropic axis were determined before surgery as well as 3 and 6 months after electrode implantation. In addition, 24-hour cortisol profiles and dexamethasone suppression tests were obtained. Postoperative hormone changes were correlated with individual neuropsychological test performance, psychiatric status and anthropometric measures. RESULTS: While PD patients experienced weight gain (p = 0.025) at follow-up, most neuropsychological data and basal HP hormone levels did not change over time. HPA regulation and diurnal rhythmicity of cortisol remained intact in all patients. The 24-hour mean cortisol levels decreased 6 months after surgery (p = 0.002) correlating with improved postoperative depression (p = 0.02). CONCLUSIONS: Chronic application of high-frequency electrical stimuli in the STN was not associated with HP dysfunction in patients with advanced PD. The diurnal variability of peripheral cortisol secretion as one important element of the endogenous biological clock remained intact. Evening cortisol levels decreased after surgery reflecting a favorable regulation of the cortisol setpoint. STN-DBS can be considered safe from a neuroendocrine perspective, but the origin of unwanted side effects warrants further elucidation.

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.

Interleukin-1ß 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-1ß 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-1ß 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-1ß 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.

Changes in the sex hormone profile of male patients with moderate-to-severe plaque-type psoriasis under systemic therapy: results of a prospective longitudinal pilot study.

Patients with moderate-to-severe plaque-type psoriasis exhibit increased cardiovascular mortality. Recent publications point towards psoriasis-induced insulin resistance as an important pathomechanism driving cardiovascular comorbidity in these patients. As the hormonal status in general and sex hormone-binding globulin (SHBG) in particular serve as sensitive indicators for insulin resistance, we analysed these parameters in the context of a set of multiple additional clinical and laboratory measurements in a cohort of male patients. Of 33 consecutively enrolled male patients receiving continuous systemic therapy for their moderate-to-severe plaque-type psoriasis, 23 male patients for whom all parameters could be collected over a 24-week treatment period were included in this analysis. At baseline, testosterone levels varied between 212 and 660 ng/ml (median: 377.0), and SHBG between 11.9 and 46.0 nmol/l (median: 29.2), thus documenting lack of hypogonadism among these patients. Clinically, 19/23 patients experienced at least a 50% reduction in their PASI under therapy. Using a multivariate regression model to further analyse the sub-group of patients responding to treatment, hs-CRP, PASI, leptin and resistin all improved under effective systemic anti-inflammatory therapy, thus losing their significant influence on SHBG. SHBG performed well as a sensitive biomarker for insulin resistance and systemic inflammation in these patients. Its improvement, as well as the reduction of resistin serum levels, most likely reflects a state of reduced cardiovascular risk in patients undergoing effective continuous systemic therapy. Long-term safety data, generated e.g. from psoriasis registries, are needed to assess whether this effect translates into reduced cardiovascular mortality.

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

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.

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

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.

Pituitary function and IGF-I levels following ischemic stroke.

BACKGROUND: Pituitary dysfunction is a known complication of traumatic brain injury and subarachnoidal hemorrhage but there are few data about pituitary dysfunction as a complication of ischemic stroke. METHODS: We prospectively studied patients 66-274 days after an ischemic stroke, evaluating the prevalence of pituitary dysfunction (by combined releasing hormone testing: GHRH, CRH), stroke severity, outcome and incidence of anxiety and depression. RESULTS: Thirty-two patients (82%) presented with some degree of pituitary dysfunction with predominantly impaired growth hormone response (79.5%) and secondary adrenal failure (14.6%). Abnormal anxiety and/or depression was found in 28.3 and 32.7% of the patients. NIHSS (National Institute of Health Stroke Scale) varied between 1 and 15. Improvement in neurological deficit (ΔNIHSS) correlated significantly with NIHSS at baseline (p < 0.001) but not with pituitary function. CONCLUSIONS: Patients with ischemic stroke may suffer from pituitary dysfunction with predominantly impaired growth hormone response and secondary adrenal failure. We suggest that patients who suffer from stroke should undergo pituitary testing.

Systemic therapy of plaque-type psoriasis ameliorates endothelial cell function: results of a prospective longitudinal pilot trial.

Severe psoriasis is associated with significant cardiovascular mortality. We therefore investigated the effects of systemic therapy on the cardiovascular risk of psoriasis patients. Thirteen consecutive patients receiving fumaric acid esters were included and followed for 24 weeks both clinically and by means of laboratory monitoring, 10 completed the study. Eight of ten patients showed a PASI-50 response. Two of three patients with clinical insulin resistance (Homeostasis Model Assessment of insulin resistance >2.5) showed normal insulin responsiveness at the end of the study. Clinical improvement was paralleled by a reduction of high-sensitive CRP serum levels (median -25%). There was a trend toward reduced serum levels for the vascular endothelial growth factor (median -10%) and resistin (median -4%), while the potentially cardio-protective adiponectin showed a trend toward increased serum levels under therapy (median +19%). Systemic endothelial function assessed by venous occlusion plethysmography revealed an improvement of endothelial vasodilator function after 24 weeks of treatment (p < 0.02). This is the first prospective study documenting an amelioration of endothelial cell function in patients with moderate-to-severe plaque-type psoriasis under effective continuous systemic therapy. Future studies need to compare the cardioprotective effects of different treatment modalities, based on hard end points such as the rate of myocardial infarction.

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

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.

Anti-inflammatory effects of the GABA(B) receptor agonist baclofen in allergic contact dermatitis.

The gamma amino butyric acid B (GABA(B)) receptor is a G protein-coupled receptor (GPCR) involved in synaptic transmission. Recent data indicate it to be also expressed on immune cells, along with chemokine receptors, which are also GPCRs. As GPCRs can undergo heterologous desensitization, we have examined the ability of baclofen, a GABA(B) receptor selective agonist, to interfere with the function of pro-inflammatory chemokine receptors known to be upregulated in cutaneous inflammation. In vitro, baclofen reduces chemotaxis of human peripheral blood mononuclear cells towards CCL2, CCL5, CXCL10, CXCL2 and CX3CL1 in a dose-dependant manner. Protein kinase C inhibitors calphostin C and G0 6976 could reverse this effect, pointing towards the involvement of both calcium-dependent and -independent protein kinase C in baclofen-induced inhibition of chemokine receptors. In an in vivo model of contact hypersensitivity in C57BL/6 mice, intraperitoneal injection of baclofen markedly alleviated signs of inflammation as well as recruitment of neutrophils, monocytes and lymphocytes into the skin. This study demonstrates a new role for the GABA(B) receptor in inflammation, making it a potential new therapeutic target to treat inflammatory skin diseases.

Research in practice: the systemic aspects of psoriasis.

Psoriasis is a common, chronic inflammatory and frequently severe skin disease. Recent epidemiologic studies have documented an increased cardio-vascular mortality in psoriasis patients. Our own work focuses on endothelial cells as mediators for the development of inflammatory infiltrates and more recently as a victim of injury caused by infiltrating cells. In this context, we have measured systemic effects of this seemingly cutaneous inflammation, which results in a metabolic state much like that in patients developing diabetes mellitus and insulin resistance. The latter is an important pathomechanism causing endothelial cell dysfunction and subsequently cardiovascular diseases such as myocardial infarction or stroke. Co-morbidities observed in psoriatic patients therefore represent complications of the accompanying systemic inflammation and are likely to be mediated through the mechanism of insulin resistance. As psoriasis is a risk factor for cardiovascular diseases, its adequate management must include the treatment of other known risk factors. Dermatologists should discuss the elevated cardiovascular risk with their psoriasis patients and encourage them not to smoke and to normalize their body weight.

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.