Emerging treatments in the management of psoriasis: biological targeting with ustekinumab

Psoriasis is a chronic, genetically determined, immune-mediated, inflammatory skin disease affecting approximately 2% to 3% of Caucasian population. Given the well-established role of the immuno-mediated inflammation in the pathogenesis of psoriasis, in the past few years several key steps in the pathogenesis of this disease have been elucidated and the increased knowledge led to the development of specific drugs, commonly defined as “biologics” targeting one or more of these steps. At present an anti-CD11a antibody (efalizumab), an anti-LFA3/CD2 receptor (alefacept) and 3 antitumor necrosis factor alpha agents (adalimumab, etanercept, infliximab) are now commercially available for the treatment of both psoriasis and psoriatic arthritis. Recent studies have demonstrated that interleukins (IL) 12 and 23 play an important role in the pathophysiology of psoriasis. In fact members of the IL-12 family of cytokines have the potential to act as the next major cytokine(s) in pathogenesis and the treatment of psoriasis. Ustekinumab (CNTO 1275, Centocor Inc, Malvern, PA, USA) is a human monoclonal antibody that binds to the shared p40 protein subunit of human interleukins 12 and 23 with high affinity and specificity, thereby preventing interaction with their surface IL-12Rβ1 receptor. Different clinical studies have been conducted to date. In particular a phase II study and two phase III studies, PHOENIX 1 together with PHOENIX 2, show very encouraging results. This review reports on the latest progress made in the clinical use of biologic drugs for psoriasis focusing on the new human IL-12/23 monoclonal antibody, ustekinumab, for psoriasis

Cutaneous lymphomas: proposal for new classification

Dosedanje klasifikacije kožnih limfomov (npr. Kielska) so temeljile na njihovih histoloških značilnostih in niso razlikovale med primarnimi in sekundarnimi kožnimi limfomi, zaradi česar imajo majhno praktično vrednost. Nova klasifikacija kožnih limfomov zato temelji na kombinaciji kliničnih, histoloških, imunohistokemičnih in genetskih kriterijev in daje smernice za zdravljenje vsakega posameznega bolnika. Limfome razvršča najprej na T- in B-celične, nato pa glede na potek in prognozo na indolentno, intermediarno, agresivno ter provizorično skupino.The currently used classifications of cutaneous lymphomas, such as that of Kiel, are based on their histologic characteristic, not distinguishing betweenprimary and secondary cutaneous lymphomas. Therefore, their practical value is limited. The new classification combines clinical, histologic, immunohistochemical and genetic criteria which instruct the treatment of the individual patient. Lymphomas are divided into T and B-cell types, and to the respect of their evolution and prognosis the indolent, intermediate, agressiveand provisory group are defined

Use of Vitamins and their Derivates in the Treatment of Cutaneous Disorders

Vitamins represent fundamental substrates for various physiologic functions occurring in human body. This review seeks to highlight their relevance in skin biology and to describe the cutaneous manifestations correlated with their deficiency

Infliximab in the treatment of plaque type psoriasis

Psoriasis is a chronic and immunomediated skin disease characterized by erythematous scaly plaques. Psoriasis affects approximately 1% to 3% of the Caucasian population. Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine that plays a critical role in the pathogenesis of psoriasis. Infliximab is an anti-TNF-α drug widely used for the treatment of plaque type psoriasis and psoriatic arthritis. Controlled clinical trials demonstrated that infliximab is characterized by a high degree of clinical response in moderate to severe plaque psoriasis. Moreover infliximab showed rapid efficacy in nail psoriasis which represents a therapeutic challenge for dermatologists and a relevant source of distress for patients with plaque psoriasis. This anti-TNF-α has an encouraging safety profile, especially as long as physicians are watchful in prevention and early diagnosis of infections and infuse reactions. The efficacy, tolerability and safety profiles suggest infliximab as a suitable anti-psoriatic drug in the long-term treatment of a chronic disease such as plaque-type psoriasis

Effect of bradykinin on nitric oxide production, urea synthesis and viability of rat hepatocyte cultures

BACKGROUND: It is well known that cytotoxic factors, such as lipopolysaccharides, derange nitrogen metabolism in hepatocytes and nitric oxide (NO) is involved among the other factors regulating this metabolic pathway. Hepatocytes have been shown to express large levels of NO following exposure to endotoxins, such as bacterial lipopolysaccharide and/or cytokines, such as tumour necrosis factor-α (TNFα), interleukin-1. The control role of arginine in both urea and NO biosynthesis is well known, when NO is synthesized from arginine, by the NOS reaction, citrulline is produced. Thus, the urea cycle is bypassed by the NOS reaction. Many authors demonstrated in other cellular types, like cardiomyocytes, that bradykinin caused the increase in reactive oxygen species (ROS) generation. The simultaneous increase of NO and ROS levels could cause peroxynitrite synthesis, inducing damage and reducing cell viability. The aim of this research is to study the effect of bradykinin, a proinflammatory mediator, on cell viability and on urea production in cultures of rat hepatocytes. RESULTS: Hepatocytes were treated with bradykinin, that stimulates nitric oxide synthase (NOS). NO release was determined using 4,5 diaminofluorescein diacetate (DAF-2DA), as fluorescent indicator of NO. Addition of the NOS inhibitor, N(g)-nitro-L-arginine methyl ester (L-NAME), to the culture medium inhibited the increase of NO production. Exposure of hepatocytes to bradykinin 0,1 mM for 2 hours resulted in a significant decrease of urea synthesis. Cell viability, instead, showed a significant decrease 24 hours after the end of bradykinin treatment as determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5diphenyl-2H-tetrazolium (MTT) assay. L-NAME addition recovered urea production and cell viability at control values. CONCLUSION: The findings suggest that the cell toxicity, after bradykinin treatment, effectively depends upon exposure to increased NO levels and the effects are prevented by L-NAME. The results show also that the increased NO synthesis induces a reduced urea production, that is another index of cell damage

Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

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Metabolic abnormalities associated with initiation of systemic treatment for psoriasis: evidence from the Italian Psocare Registry.

Objective To evaluate variations in laboratory parameters and diagnoses of selected clinical conditions up to16 weeks after starting a new systemic psoriasis treatment for Psocare Registry enrollees.Design Prospective cohort study.Setting Italian public referral centres for psoriasis treatment.Patients First-time recipients (n = 10,539) of continuous systemic psoriasis treatment for at least 16 weeks.Main outcome measure Mean variations in (weeks 8 and 16) and proportions of patients reaching a clinicallymeaningful increase in serum levels (week 16) of total and low-density lipoprotein cholesterol, triglycerides, aspartateamino transferase, alanine amino transferase and creatinine, as well as week-16 cumulative incidences of newdiagnoses of diabetes mellitus and arterial hypertension.Results Mean cholesterol and triglyceride levels significantly increased in patients treated with acitretin orcyclosporine. Mean triglyceride levels also increased in efalizumab- and etanercept-treated patients. Meantransaminase values increased in methotrexate-treated patients, and mean aspartate amino transferase levelsincreased in infliximab-treated patients. The average serum creatinine value increased in cyclosporine-treatedpatients. Acitretin and cyclosporine were associated with risk of hypercholesterolaemia (odds ratios 1.51 and 1.34)and acitretin with risk of hypertriglyceridaemia (odds ratio 1.43). Methotrexate and infliximab were associated withrisk of more than doubling the upper normal aspartate amino transferase (odds ratios 2.06 and 1.87) and alanineamino transferase (odds ratios 2.38 and 1.74) values. The relative risk of developing arterial hypertension anddiabetes was increased for patients receiving cyclosporine (odds ratios 3.31 and 2.88).Conclusion Systemic treatments for psoriasis resulted in heterogeneous effects on the parameters analysed.Received: 1 September 2011; Accepted: 12 January 201

Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1)

BackgroundApremilast works intracellularly to regulate inflammatory mediators.ObjectiveESTEEM 1 evaluated efficacy/safety of apremilast at 30 mg twice a day for moderate to severe plaque psoriasis.MethodsThis phase III, multicenter, double-blind, placebo-controlled study randomized adults (2:1) to apremilast or placebo. At week 16, the placebo group switched to apremilast through week 32, followed by a randomized treatment withdrawal phase to week 52. Binary end points were analyzed using χ2 test; continuous end points used analysis of covariance.ResultsIn all, 844 patients were randomized (n = 282, placebo; n = 562, apremilast). At week 16, significantly more patients taking apremilast achieved 75% or greater reduction from baseline Psoriasis Area and Severity Index score (PASI-75) (33.1%) versus placebo (5.3%, P < .0001; primary end point). Most (61.0%) patients rerandomized to apremilast at week 32 achieved PASI-75 at week 52 versus 11.7% rerandomized to placebo. Of patients rerandomized to apremilast at week 32, mean percentage change from baseline PASI score was −88% to −81% (weeks 32-52). During the placebo-controlled period, 55.7% and 69.3% of patients randomized to placebo and apremilast, respectively, had 1 or more adverse events. Most adverse events were mild/moderate in severity. No new significant adverse events emerged with continued apremilast exposure versus the placebo-controlled period.LimitationsData were limited to 52 weeks and may not generalize to nonplaque psoriasis.ConclusionsApremilast was effective in moderate to severe plaque psoriasis