Mechanism of pathogenesis of imiquimod‐induced skin inflammation in the mouse: A role for interferon‐alpha in dendritic cell activation by imiquimod

Topical application of imiquimod (IMQ), a Toll‐like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ‐induced psoriasis‐like skin inflammation, T‐helper (Th)17 cells and interleukin (IL)‐17/IL‐22‐producing γδ‐T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis‐like skin inflammation by IMQ treatment remain unclear. In this study, we investigated pathogenic mechanisms of IMQ‐induced psoriasis‐like skin inflammation in mice. We first confirmed that, together with an increase in IL‐17 and IL‐22 production, application of IMQ to mouse skin induced the expression of cytokines required for activation of the Th17 pathway, and pro‐inflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7^?/? mice demonstrated that most of the in vivo effects of IMQ were mediated via TLR7. In an in vitro study using plasmacytoid dendritic cells (DCs), IMQ induced production of interferon (IFN)‐α, IL‐23, IL‐6 and tumor necrosis factor (TNF)‐α. Furthermore, when we analyzed in vitro‐generated bone marrow‐derived DCs with features similar to TNF‐α and inducible nitric oxide synthase (iNOS)‐producing DCs, IL‐23, IL‐6, IL‐1β, TNF‐α and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co‐stimulation with IMQ and IFN‐α. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN‐α was suggested to be caused by upregulation of TLR7 expression by IFN‐α. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasis‐like skin inflammation are induced by IMQ and IFN‐α in a mouse model.     

Etanercept suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of interleukin (IL)-19, IL-20 and IL-24

Background  Psoriasis is a Th17/Th1‐mediated skin disease that often responds to antitumour necrosis factor (TNF)‐α therapies, such as etanercept. Objectives  To better define mechanisms by which etanercept improves psoriasis and to gain insight into disease pathogenesis. Methods  We investigated the early biochemical and cellular effects of etanercept on skin lesions in responder patients prior to substantial clinical improvement (≤ 4 weeks). Results  By 1 week, etanercept acutely suppressed gene expression of the interleukin (IL)‐20 subfamily of cytokines (IL‐19, IL‐20, IL‐24), which were found to be predominantly epidermis‐derived and which are implicated in stimulating epidermal hyperplasia. Additionally, by 1 week of therapy, suppression of other keratinocyte‐derived products (chemokines, antimicrobial proteins) occurred, while suppression of epidermal regenerative hyperplasia occurred within 1–3 weeks. Th17 elements (IL‐23p19, IL‐12p40, IL‐17A, IL‐22) were suppressed by 3–4 weeks. In vitro, TNF‐α and IL‐17A coordinately stimulated the expression of the IL‐20 subfamily in normal keratinocytes. Conclusions  Based on the rapid suppression of regenerative hyperplasia, chemokines and other keratinocyte‐derived products, including the IL‐20 subfamily, we propose that epidermal activation is a very early target of etanercept. As many of these keratinocyte markers are stimulated by TNF‐α, their rapid downregulation is likely to reflect etanercept’s antagonism of TNF‐α. Additionally, decreased epidermal hyperplasia might result specifically from acute suppression of the IL‐20 subfamily, which is also a likely consequence of etanercept’s antagonism of TNF‐α. Thus, the IL‐20 subfamily has potential importance in the pathogenesis of psoriasis and therapeutic response to etanercept.     

IL‐33 is secreted by psoriatic keratinocytes and induces pro‐inflammatory cytokines via keratinocyte and mast cell activation

IL‐33 is a novel pro‐inflammatory cytokine and ligand for the orphan receptor ST2. Although originally defined as an inducer of Th2‐mediated responses, IL‐33 was recently found to be involved in arthritis, a Th1/Th17‐mediated disease. Here, we assessed the ability of IL‐33 to promote inflammation via mast cells (MCs) and keratinocytes (KCs) activation in psoriasis. IL‐33 resulted elevated in the skin but not in the serum of psoriasis patients. IL‐33 was secreted by psoriasis KCs and HaCaT cells after TNF‐α stimulation. In HMC‐1, TNF‐α, but not IL‐17, could induce a robust increase in IL‐33 expression. In HaCaT cells, TNF‐α was able to induce IL‐6, MCP‐1 and VEGF, and the addition of IL‐33 reinforced these increases. TNF‐α + IL‐33 combination showed similar results in primary KCs and ex vivo skin organ culture. In conclusion, our study suggests that IL‐33 may be involved in psoriasis biology via MCs and KCs.     

Topical silver and gold nanoparticles complexed with Cornus mas suppress inflammation in human psoriasis plaques by inhibiting NF‐κB activity

New biomaterials based on nanoparticles (NPs) carrying polyphenols‐rich extracts (Cornus mas) recently showed promising anti‐inflammatory activity in psoriasis. We aimed to understand how topically delivered silver and gold nanoparticles complexed with Cornus mas (Ag‐NPs‐CM, Au‐NPs‐CM) modulate inflammation in psoriasis at cellular and molecular level. The impact on psoriatic inflammation was assessed in vitro on pro‐inflammatory macrophages, by clinical score, high‐frequency ultrasonography and immunohistology of psoriasis plaques treated with Ag‐NPs‐CM, Au‐NPs‐CM or control. Incubation of pro‐inflammatory macrophages with nanoparticles significantly decreased the release of NO, IL‐12 and TNF‐α. Immunofluorescence confirmed that nanoparticles significantly reduced CD68‐positive macrophages and their IL‐12 and TNF‐α production in human psoriasis plaques. NPs‐CM appear to repress NF‐κB activation in macrophages, inhibiting the production of pro‐inflammatory factors with causal role in psoriasis. Ag and Au NPs‐CM represent a novel nanoparticle‐based “green” technology which may provide an efficient tool for modern psoriasis therapy, circumventing immunosuppression‐related side effects of biologicals.     

The role of human 6‐sulfo LacNAc dendritic cells (slanDCs) in autoimmunity and tumor diseases

Dendritic cells play a central role in the regulation of immunological reactivity. The existence of functionally specialized populations of dendritic cells in the skin is a consequence of qualitatively different attacks on our organism. slanDCs are human inflammatory dendritic cells that are characterized by the specific expression of the carbohydrate 6‐sulfo LacNAc (slan). After phenotypic maturation, slanDCs are capable of producing very high amounts of proinflammatory mediators such as IL‐12, TNF‐α, IL‐1β and IL‐23. Recent data describe a potential role of slanDCs in a number of different diseases like psoriasis, lupus erythematosus, and tumors, thus opening up new areas of research on their respective pathogenesis. Furthermore, a slanDC‐specific targeting system has been developed as a basis for direct therapeutic manipulation. Future challenges of slanDC research include deepening our understanding of the significance of slanDCs in the regulation of adaptive and innate immune responses, as well as translating this knowledge into therapeutic options.     

Interleukin (IL)‐22, IL‐17, IL‐23, IL‐8, vascular endothelial growth factor and tumour necrosis factor‐α levels in patients with psoriasis before,during and after psoralen–ultraviolet A and narrowband ultraviolet B therapy

Background Several cross‐sectional studies have shown that different cytokines and growth factors are enhanced in psoriasis. Objectives We aimed to understand the role/relation of interleukin (IL)‐22, IL‐17, IL‐23, IL‐8, vascular endothelial growth factor (VEGF) and tumour necrosis factor (TNF)‐α in psoriasis vulgaris, addressing their levels and changes before, during and after psoralen–ultraviolet A (PUVA) and narrowband ultraviolet B (NB‐UVB) treatment. Methods A cross‐sectional and a longitudinal study (n = 34) – before (T0) and at 3 (T3), 6 (T6) and 12 (T12) weeks of NB‐UVB and PUVA therapy – were performed; 17 patients started NB‐UVB and 17 PUVA, and IL‐22, IL‐17, IL‐23, IL‐8, TNF‐α and VEGF levels were evaluated. Results At T0, compared with controls (n = 20), all the parameters were significantly higher in patients, except for TNF‐α. Both NB‐UVB and PUVA treatment gave, at T3, a significant decrease in TNF‐α and IL‐23; IL‐22 and IL‐17 decreased significantly at T6; all parameters and Psoriasis Area and Severity Index decreased significantly at T12. However, in both groups, at T12, VEGF was still significantly higher than control. Conclusions Psoriasis seems to be a complex disease in which the cytokine network is disturbed, namely in levels of IL‐22, IL‐17, IL‐23, IL‐8, TNF‐α and VEGF. NB‐UVB and PUVA follow‐up studies suggested that the reduction in the IL‐23/Th17 axis might be important in the pathogenic mechanisms of psoriasis. Further follow‐up studies of patients with psoriasis treated with these and other therapies could be very helpful for the understanding of the disturbance in the cytokine network in psoriasis and indirectly in its pathogenesis.     

Secondary failure of TNF‐α inhibitors in clinical practice

Tumor necrosis factor alpha (TNF‐α) is a leading inflammatory cytokine that plays a pivotal role in the pathogenesis of psoriasis. In case of a severe course of psoriasis and moderate‐to‐severe disease in which traditional systemic treatments are ineffective or contraindicated, TNF‐α inhibitors (iTNF‐α) are used. This class of drugs includes monoclonal antibodies and a fusion protein (etanercept) and can induce a humoral or cell‐mediated immune response, leading to formation of anti‐drug antibodies (ADAs). The immunogenicity may affect iTNF‐α drug pharmacokinetics, which would lead to hampering the clinical response (secondary drug failure), so a need to increase the drug dose arises. Antibodies against monoclonal antibodies (adalimumab, infliximab) have been associated with diminished clinical response, while against etanercept are non‐neutralizing and appear to have no significant effect on clinical response and treatment safety. Switching of biologic agents may be one strategy in ADA‐associated secondary failure of iTNF‐α. However researches are needed to identify risk factors for ADA development and investigate management strategies for optimized treatment response. The authors reviewed the literature on the effectiveness of iTNF‐α and pointed out the prevention of secondary failure in clinical practice.     

Cutaneous vascular patterns in psoriasis

Microvascular abnormalities are a characteristic feature of psoriasis and play a crucial role in its pathogenesis. Investigational studies have shown that activated keratinocytes in lesional skin undergo an accelerated epidermal cell turnover and are a major source of pro‐angiogenic cytokines, like as VEGF, ESAF, PDECGE/TP, TNF‐α, TGF‐α and PDGF, suggesting that the epidermis is capable of inducing vascular proliferation. On the other hand, microvascular alterations are essential for the development and persistence of the psoriatic lesions as they provide cellular and tissue nutrition to hyperplastic keratinocytes and promote inflammatory cell migration. Also, dilated and slightly tortuous blood vessels within dermal papillae represent one of the earliest detectable histological changes for all stages of lesional development. Videodermatoscopy is a new non invasive imaging technique able to identify modifications of microvascular architecture in vivo and such evaluation will be useful for the dermatologist both for diagnostic and prognostic evaluation, as well as for post‐therapeutic follow‐up. In this review, the role of microvascular abnormalities in the pathogenesis of psoriasis as well as the mechanisms underlying vascular changes and their primary therapeutic implications will be reviewed and discussed.     

Circulating adipokine levels in Portuguese patients with psoriasis vulgaris according to body mass index,severity and therapy

Background Psoriasis vulgaris is associated with overweight/obesity and with increased C‐reactive protein (CRP), tumour necrosis factor (TNF)‐α, interleukin (IL)‐6, leptin and resistin levels and decreased adiponectin levels. Objectives To understand the role/relationship of adipokines, as well as CRP, in a Portuguese psoriatic population, by assessing the relationship of their levels with psoriasis severity, defined by Psoriasis Area and Severity Index (PASI), with obesity, defined by body mass index (BMI), and psoriasis therapy. Methods A cross‐sectional (n = 66) and longitudinal study (before and after 12 weeks of therapy; n = 44) was performed; 10 patients started topical treatment, 17 narrow‐band ultraviolet B (NBUVB) and 17 psolaren associated with UVA (PUVA). Results Patients presented significantly higher BMI, leptin, resistin, TNF‐α, IL‐6 and CRP and significantly lower adiponectin values. CRP and IL‐6 correlated with PASI. Adiponectin and leptin were more altered in patients with higher BMI. Concerning severity, CRP, resistin and adiponectin were more altered in the severer forms. After treatment, a significant reduction in PASI, CRP, resistin, TNF‐α and IL‐6, and a significant rise in adiponectin were observed. Nonetheless, CRP and adiponectin remained different from those of control. Concerning therapies, topical therapy was not associated with any significant change, except for TNF‐α. After NBUVB, a significant reduction was observed in TNF‐α and in CRP. For PUVA, we observed a significant reduction in TNF‐α, IL‐6 and CRP, and a significant increase in adiponectin. Conclusion In psoriatic patients, increased overweight/obesity was associated with raised leptin levels and decreased adiponectin levels. Leptin may contribute to enhance the inflammatory process in overweight/obese psoriatic patients. Resistin, IL‐6, CRP and adiponectin levels appear to be dependent on psoriasis severity. CRP, together with IL‐6, appears to be a useful marker of psoriasis severity. Both NBUVB and PUVA were effective; however, PUVA results seem to be more successful. Nonetheless, after NBUVB and PUVA, a low‐grade inflammation still persists.     

Impact of etanercept treatment on ultraviolet B-induced inflammation, cell cycle regulation and DNA damage

Background Current studies indicate that treatment with tumour necrosis factor (TNF)‐α blockers plus ultraviolet (UV) B phototherapy results in higher relative Psoriasis Area and Severity Index reduction as compared with TNF‐α monotherapy. Objectives This study aimed to investigate the acute impact of etanercept on UVB‐induced inflammation, cell cycle regulation and DNA damage. Methods Eleven subjects diagnosed with psoriasis who fulfilled the indication criteria for etanercept treatment were studied. A healthy skin site on the upper back was treated with UVB at 2 minimal erythema doses (MED). After 1, 24 and 72 h punch biopsies were taken from this site. Following the 72 h biopsy etanercept 50 mg was administered subcutaneously. After 48 h, 2 MED was given on healthy skin adjacent to previously treated skin sites. Again, after 1, 24 and 72 h punch biopsies were taken from this site. UVB‐ as well as UVB plus etanercept‐treated skin was assessed by means of colorimetry and immunohistochemical studies for caspase 3, cyclin D₁, interleukin‐12, Ki‐67, p16, p53, survivin, thymine dimers and TNF‐α. Results Erythema formation did not differ significantly between UVB‐ and UVB plus etanercept‐treated sites. Comparisons between UVB‐ and UVB plus etanercept‐treated sites at a given time (1, 24, 72 h) did not result in significant differences in immunoreactivity of the markers investigated, except for cyclin D₁, p53 and survivin. Immunoreactivity of cyclin D₁ and p53 was significantly decreased in UVB plus etanercept‐treated sites at 24 h. Survivin expression was significantly higher in UVB plus etanercept‐treated skin as compared with UVB monotherapy. Conclusions Our data indicate that combined treatment with broadband UVB and TNF‐α blockers might increase the risk of photocarcinogenesis by influencing apoptotic as well as antiapoptotic pathways.     

Development of cutaneous sarcoidosis during treatment with tumour necrosis alpha factor antagonists

The use of tumour necrosis factor alpha (TNF‐α) antagonists is increasing in the field of dermatology. These agents have been used for multiple inflammatory and immune skin conditions, but most notably, psoriasis. Adverse effects of anti‐TNF‐α agents have been reported, including the paradoxical development of sarcoidosis. We present an unusual case of limited cutaneous sarcoidosis developing while the patient was on etanercept therapy, and a review of the current literature.     

Anti–tumour necrosis factor-α therapy increases body weight in patients with chronic plaque psoriasis: a retrospective cohort study

Background Chronic plaque psoriasis is associated with overweight or obesity. Anti–tumour necrosis factor‐α (anti‐TNF‐α) treatments are now frequently used in psoriasis management. TNF‐α is deeply involved in body weight homeostasis, which may be affected by TNF‐α–targeted therapy. Objective To investigate whether anti‐TNF‐α treatments is associated with changes in body weight in patients with chronic plaque psoriasis. Methods We performed a retrospective controlled analysis comparing the variations in body weight and body mass index (BMI) in three closed cohorts of psoriatic patients during a 6‐month treatment with etanercept (N = 58), infliximab (N = 40) or methotrexate (N = 43). Results We observed a body weight increment of 1.5 ± 2.7 kg (mean ± SD; P = 0.0002) and 2.5 ± 3.3 kg (P = 0.004) in patients treated with etanercept and infliximab, respectively. In contrast, a non‐significant change (0.6 ± 1.4 kg; P = 0.4) was measured in patients treated with methotrexate. The BMI increased with 0.5 ± 0.5 (P = 0.01) and 0.8 ± 1 (P = 0.003) points in patients treated with etanercept and infliximab, respectively, whereas it did not change (< 0.2 ± 0.5; P = 0.06) in patients treated with methotrexate. About one fourth of patients experienced a 4‐ to 10‐kg weight gain. Differences in body weight variations among patients treated with anti‐TNF‐α therapies and methotrexate were statistically significant (P = 0.0005). We could not identify clinical parameters predicting this phenomenon. Conclusions Patients with psoriasis treated with long‐term anti‐TNF‐α therapies may manifest a body weight gain. This effect should be taken into account in the global approach to patients with psoriasis.     

CCL7 contributes to the TNF‐alpha‐dependent inflammation of lesional psoriatic skin

Chemokines are small chemotactic proteins that have a crucial role in leukocyte recruitment into tissue. Targeting these mediators has been suggested as a potential therapeutic option in inflammatory skin diseases such as psoriasis. Using quantitative RT‐PCR, we found CCL7, a chemokine ligand known to interact with multiple C‐C chemokine receptors, to be markedly increased in lesional psoriasis as opposed to atopic dermatitis, lichen planus, non‐lesional psoriatic and normal control skin. Surprisingly, this increase in CCL7 mRNA expression exceeded that of all other chemokines investigated, and keratinocytes and dermal blood endothelial cells were identified as its likely cellular sources. In an imiquimod‐induced psoriasis‐like mouse model, CCL7 had a profound impact on myeloid cell inflammation as well as on the upregulation of key pro‐psoriatic cytokines such as CCL20, IL‐12p40 and IL‐17C, while its blockade led to an increase in the antipsoriatic cytokine IL‐4. In humans receiving the TNF‐α‐blocker infliximab, CCL7 was downregulated in lesional psoriatic skin already within 16 hours after a single intravenous infusion. These data suggest that CCL7 acts as a driver of TNF‐α‐dependent Th1/Th17‐mediated inflammation in lesional psoriatic skin.     

Development of MGUS in psoriatic patients: a possible undiagnosed event during anti‐TNF‐α‐treatment

Background Monoclonal gammopathies are haematological conditions characterized by the clonal proliferation of plasma cells which produce a monoclonal immunoglobulin that accumulates in the blood. They have already been reported during treatment with a range of drugs but never before during treatment with the anti‐TNF‐α treatments: adalimumab, etanercept and infliximab currently used in the therapy of moderate‐severe psoriasis and psoriatic arthritis. Objective This is a case series describing the development of MGUS in psoriatic patients treated with anti‐TNF‐α. Methods Three hundred patients receiving an anti‐TNF‐α treatment for chronic plaque psoriasis or psoriatic arthritis in a clinical setting in Italy, These patients were screened through serum protein electrophoresis to investigate the possible development of MGUS. Results Eight patients were found to have developed monoclonal gammopathy of undetermined significance. The median treatment duration for the eight patients was 1 year with excessive IgG present in five patients, IgM accumulation in one patient and a double monoclonal component in two patients. Conclusion Our data suggest that there may be an association between anti‐TNF‐α therapy and development of MGUS.     

Human 6-sulfo LacNAc (slan) dendritic cells are a major population of dermal dendritic cells in steady state and inflammation

Background. The immune system of the skin has a network of resident dendritic cells (DCs) consisting of epidermal Langerhans cells and various subsets of dermal DCs. We recently reported on a new population of dermal DCs, called slan (6‐sulfoLacNAc+) DCs, which have a potent capacity to stimulate Th17/Th1 T‐cell responses. Aim. To understand the characteristics of slanDCs as a new population of dermal DCs in the context of other DC populations in healthy and psoriatic skin. Methods. We immunofluorescently stained skin samples from healthy controls and from patients with psoriasis. Results. Staining healthy skin for DCs showed that slanDCs (CD1a? CD1c? CD11c? CD14? CD163?) were present at a similar frequency to that of CD1c+ CD11c+ CD1a+ CD14? CD163? dermal DCs, which have previously been regarded as the major population of resident DCs. In psoriatic skin, the frequency of slanDCs and CD1c+ DCs was doubled, and the slanDCs expressed CD11c. In‐depth analysis of DCs in psoriatic skin by four‐colour immunofluorescence analysis showed that the pool of CD11c+ cells could be further subdivided into CD11c+ CD14+ CD163? DCs and CD11c+ CD163+ CD14+ macrophages. Conclusion. SlanDCs, initially described as large population of proinflammatory DCs in blood, are a novel and major part of the resident dermal myeloid DC system in both healthy and inflamed skin.     

S‐allyl cysteine inhibits TNF‐α‐induced inflammation in HaCaT keratinocytes by inhibition of NF‐ κB‐dependent gene expression via sustained ERK activation

Tumor necrosis factor‐α (TNF‐α)‐induced keratinocyte inflammation plays a key role in the pathogenesis of multiple inflammatory skin diseases. Here we investigated the anti‐inflammatory effect of S‐allyl cysteine (SAC) on TNF‐α‐induced HaCaT keratinocyte cells and the mechanism behind its anti‐inflammatory potential. SAC was found to inhibit TNF‐α‐stimulated cytokine expression. Further, SAC was found to inhibit TNF‐α‐induced activation of p38, JNK and NF‐κB pathways. Interestingly, SAC was found to differentially regulate ERK MAP kinase in cells. TNF‐α‐induced transient ERK activation and SAC treatment resulted in sustained ERK activation both in the presence and absence of TNF‐α. Additionally, SAC failed to inhibit the TNF‐α‐induced expression of the pro‐inflammatory cytokines TNF‐α and IL‐1β when cells were treated with the MEK inhibitor PD98059, suggesting that the anti‐inflammatory effect of SAC is via sustained activation of the ERK pathway. Since ERK activation has been reported to negatively regulate NF‐κB‐driven gene expression and we find that SAC activates ERK and negatively regulates NF‐κB, we investigated whether there existed any crosstalk between the ERK and the NF‐κB pathways. NF‐κB‐dependent reporter assay, visualization of the nuclear translocation of NF‐κB‐p65 subunit and determination of the cellular levels of I‐κB, the inhibitor of NF‐κB, revealed that SAC inhibited TNF‐α‐induced NF‐κB activation, and PD98059 treatment reversed this effect. These results collectively suggest that SAC inhibits TNF‐α‐induced inflammation in HaCaT cells via a combined effect entailing the inhibition of the p38 and the JNK pathways and NF‐κB pathway via the sustained activation of ERK.     

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)‐6, IL‐8 and tumour necrosis factor‐α

Background and objective Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro‐inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. Methods This prospective study examines the influence of MHb on serum interleukin (IL)‐6, IL‐8 and tumour necrosis tumour necrosis (TNF)‐α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. Results A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880–4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 μg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL‐6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF‐α and IL‐8 release were not found significantly increased. Three patients developed MHb concentrations >15%. Conclusions This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL‐6 but not of IL‐8 and TNF‐α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia.     

Shifting the focus – the primary role of IL‐23 in psoriasis and other inflammatory disorders

Insights into the pathophysiology of autoimmune inflammatory diseases including psoriasis have advanced considerably in recent years, and in parallel, so too have the available treatment options. Current clinical paradigms for the treatment of psoriasis have evolved to include targeted biologic therapies, starting with tumour necrosis factor‐alpha (TNF‐α) inhibitors and later, agents targeting interleukin (IL)‐12/23 and IL‐17. The most recent evidence suggests that IL‐23 might be an even more potent target for the effective treatment of psoriasis and other autoimmune inflammatory disorders. This review will describe recent developments leading to the current understanding of the key role of IL‐23 as a ‘master regulator’ of autoimmune inflammation and the clinical evidence for agents that specifically target this modulator in the context of treating psoriasis, spondyloarthropathy and inflammatory bowel disease.     

Markers of systemic inflammation in psoriasis: a systematic review and meta‐analysis

Studies investigating systemic inflammation in psoriasis use different serum markers and report discrepant results. We set out to determine whether systemic inflammation is elevated in patients with psoriasis compared with healthy controls, and to measure the extent of this elevation, by summarizing available data on serum inflammatory markers. PubMed, Embase and Web of Science were searched from inception to March 2011. We included studies comparing the serum inflammatory markers interleukin (IL)‐1β, IL‐6, IL‐10, C‐reactive protein (CRP), intracellular adhesion molecule (ICAM)‐1, E‐selectin and tumour necrosis factor (TNF)‐α in patients with psoriasis and healthy controls. Differences in serum marker levels between patients and controls were pooled as standardized mean differences (SMDs; Cohen's d) using a random‐effects model. Seventy‐eight studies were eligible. Of the 7852 individuals included, 3085 had (severe plaque) psoriasis. The pooled SMDs were higher in patients with psoriasis than in healthy controls for IL‐6 [d = 1·32, 95% confidence interval (CI) 0·83–1·81], CRP (d = 1·83, 95% CI 0·76–2·90), TNF‐α (d = 1·32, 95% CI 0·86–1·79), E‐selectin (d = 1·78, 95% CI 1·32–2·25) and ICAM‐1 (d = 1·77, 95% CI 1·15–2·39). The SMD between cases and controls for IL‐1β and IL‐10 was not significant. Age had a significant effect on the SMD for IL‐6 and TNF‐α. For IL‐6 the effect size was higher for plaque psoriasis studies (d = 1·98). The effect size was not influenced by the Psoriasis Area and Severity Index, measurement method or quality assessment. The pooled analyses suggest modest but significantly elevated levels of the proinflammatory cytokines in the serum of patients with psoriasis with predominantly severe disease. To what extent this modest increment is clinically relevant could be investigated in a synthesis of all studies measuring inflammation before and after antipsoriatic therapy.