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

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

Increased Prevalence of Metabolic Syndrome in Patients with Acne Inversa

BACKGROUND: Acne inversa (AI; also designated as Hidradenitis suppurativa) is a common chronic inflammatory skin disease, localized in the axillary, inguinal and perianal skin areas that causes painful, fistulating sinuses with malodorous purulence and scars. Several chronic inflammatory diseases are associated with the metabolic syndrome and its consequences including arteriosclerosis, coronary heart disease, myocardial infraction, and stroke. So far, the association of AI with systemic metabolic alterations is largely unexplored. METHODS AND FINDINGS: A hospital-based case-control study in 80 AI patients and 100 age- and sex-matched control participants was carried out. The prevalence of central obesity (odds ratio 5.88), hypertriglyceridemia (odds ratio 2.24), hypo-HDL-cholesterolemia (odds ratio 4.56), and hyperglycemia (odds ratio 4.09) in AI patients was significantly higher than in controls. Furthermore, the metabolic syndrome, previously defined as the presence of at least three of the five alterations listed above, was more common in those patients compared to controls (40.0% versus 13.0%; odds ratio 4.46, 95% confidence interval 2.02 to 9.96; P<0.001). AI patients with metabolic syndrome also had more pronounced metabolic alterations than controls with metabolic syndrome. Interestingly, there was no correlation between the severity or duration of the disease and the levels of respective parameters or the number of criteria defining the metabolic syndrome. Rather, the metabolic syndrome was observed in a disproportionately high percentage of young AI patients. CONCLUSIONS: This study shows for the first time that AI patients have a high prevalence of the metabolic syndrome and all of its criteria. It further suggests that the inflammation present in AI patients does not have a major impact on the development of metabolic alterations. Instead, evidence is given for a role of metabolic alterations in the development of AI. We recommend monitoring of AI patients in order to correct their modifiable cardiovascular risk factors

Toleranz von Coxiben bei Intoleranz gegenuber nicht-steroidalen Antirheumatika (NSAR)

BACKGROUND AND OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) frequently cause pseudoallergic reactions. Recognition of two different prostaglandin synthase iso-enzymes led to the development of the so-called coxibs preferentially inhibiting cyclooxygenase-2. We studied tolerability of valdecoxib preferentially inhibitng cyclooxygenase-2 in patients with a history of intolerance to NSAIDs. PATIENTS AND METHODS: 41 patients (30 female, 11male, age 14-74 years) with a history of intolerance to NSAIDs underwent scratch tests with these drugs and valdecoxib, followed by oral challenge with valdecoxib (maximum single dose: 20 mg; cumulative dose: 35mg) in a double-blind, placebo-controlled manner. RESULTS: The history of intolerance to NSAID comprised urticaria as the leading symptom (n = 26), followed by angioedema (n = 11) and anaphylactoid shock (n = 4). 21 patients reported reactions to only one NSAID, 15 identified 2 different triggering drugs, and 5 patients showed reactions to 3 different NSAIDs. Acetylsalicylic acid (n = 20) and diclofenac (n = 12) were the most frequent causative drugs. Upon oral challenge with valdecoxib, one patient developed generalized urticaria within 30 minutes following the last dose of valdecoxib; symptoms resolved after i. v. injection of 2 mg clemastine and 250 mg prednisolone. All other patients tolerated the oral challenge without adverse effects. CONCLUSION: Our results are in line with previous studies suggesting that preferential cyclooxygenase-2-inhibitors may safely be used by patients with known intolerance to NSAIDs

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

Cardiovascular morbidity in psoriasis: epidemiology, pathomechanisms, and clinical consequences

Psoriasis is a common inflammatory skin condition. Around 25% of patients develop joint involvement in the form of psoriatic arthritis as well. Recent epidemiologic studies demonstrated an increased cardiovascular morbidity among psoriasis patients. Although the association of psoriasis with cardiovascular diseases such as hypertension, myocardial infarction, and heart failure, is now widely accepted, the pathogenetic link remains yet unclear. High prevalence of the metabolic syndrome as well as adverse effects of systemic anti-psoriatic therapies may contribute to the observed association. Several pilot studies suggest that insulin resistance may contribute to the development of cardiovascular diseases in psoriasis patients who exhibit metabolic parameters like patients developing diabetes. Retrospective data provide evidence that continuous systemic therapy may reduce the risk of cardiovascular mortality in psoriasis patients. The consequences for the management of psoriasis at this point are two-fold: as co-morbidity goes along with co-medication, potential drug interactions need to be kept in mind when choosing a systemic anti-psoriatic therapy. Moreover, as psoriasis itself is a risk factor for cardiovascular morbidity, patients must avoid other known risk factors such as obesity or smoking. Dermatologists need to communicate this additional risk to their patients and support them accordingly

'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