The Advanced Treatment Of Psoriasis With New Biological Agents

Over the past three decades, laboratory and clinical research findings have shown that psoriasis is an immune-mediated skin disease in which T-cells are the primary mediators and play an important role in the process of pathogenesis .Although the nature of initial stimulating antigen in psoriasis is not known, Langerhans'cells and dermal dendritic cells capture the putative antigen, while antigen is processed and presented on the surface of the APC, maturation occurs with the expression of costimulatory molecules .The APC migrate via the afferent lymphatics to the skin-draining lymph node and present the processed antigen to naive T-cells(CD45RA+) causing T-cell maturation, activation and proliferation . Mature activated T-cells (CD45RO+) express CLA antigen — skin-homing marker CLA antigen is able to bind to E-and P-selectins expressed by endothelial cells in the dermis. This interaction stimulates T-cells to express LFA-1 and VLA-4 and endothelial cells to produce intercellular and vascular adhesion molecules (ICAM and VCAM) . The interaction of these molecules allows the activated T-cells to migrate through the postcapillary venules into the dermis. The activated T-cells can then migrate to areas of antigen expression in the dermis. The activated T-cell can secret cytokines such as IFN-r and recruit other immune effecter cells, including neutrophils.Naive T-cells need two signals to be activated. The first is the antigen presentedby APC in the context of MHCII or I ; The second one is costimulatory molecules produced on T-cells by the interaction with APC, including LFA-1 > CTLA-4, CD28 > CD2 and CD40 ligand. These bind up regulate costimulatory molecules on the APC which include ICAM-1 ^ CD86 ^ CD80 ? LFA-3 and CD40. Without the double-signal interactions, would result in T-cell anergy rather than stimulation. In the presence of IFN-y or IL-12 from the APC, T-cells differentiate into a memory (CD45RO+) Thl (helper CD4+cells) or TCI (cytotoxicCD8+cells) phenotype with expression predominantly of cytokines such as IL-2 , IFN-r and cytokine receptor IL-2R. IL-2 production in conjunction with IL-2R leads to autocrine proliferation of T-cells. In the presence of IL-10 or IL-4, T-cells differentiate into a memory(CD45RO+)Th2( helper CD4+cells)or TC2(cytotoxic CD8+cells )phenotype with expression of IL-4 IL-6 and IL-10. These activated T cells express inflammatory cytokines TNF-a and IFN-y which can induce keratinocytes to produce adhesion molecules such as ICAM-1 costimulatory molecules such as CD40 and MHC molecules for antigen presentation , facilitating further T-cell/keratinocyte interactions.TNF-a also induces keratinocytes to produce vascular endothelial cell growth factor (VEGF) which causes endothelial cell proliferation, increased ICAM/VCAM expression and subsequent increased re-ruitent of activated T-cells. Keratinocytes also produce other proflammatory cytokines such as IL-4 and IL-6 that are involved in regenerative responses. IFN-y > TNF-a that are continually produced result in a regenerative phenotype of the keratinocytes, manifested as epidermal hyperproliferation, with elongation of the rate ridges, loss of the granular and retained nuclei in the stratum corneum (parakertosis) . TNF-a also induces keratinocytes to produce IL-8 that is chemotactic for neutrophils.Biologic agents are specifically engineered to designe to block particular immunologic activation steps and the immunologic cascade associated with their activation. Four biologic agents and their targets that focus on the steps involved in the immunopathogenesis of psoriasis are: (D inhibit T-cell activation costimulation and T-cell proliferation (2) induce their destruction (3) block the effector cytokines ?cause immune deviationBlocking T-cell activation and costimulationEfalizumab: a humanized antibody to CDllaThis agent for the treatment of moderate-to-severe chronic plaque psoriasis was approved by the U.S. Food and Administration (FDA) in October 2003. This agent binds to LFA-1 on T-cell, blocks APC interaction with ICAM-1, -2 and-3, and also may block T-cell migration into skin through similar receptors expressed on endothelial cells and activated keratinocytes. Conclusion on clinical study is that efalizumab produced significant clinical and histologic improvement in psoriasis, which correlated with sustained serum efalizumab levels and T-cell CD1 la saturation and down-modulation.CTLA-4Ig: a novel soluble chimeric protein, binds to B7-l(CD80) and B7-2 (CD86) expressed on APCs and thereby inhibits a second signal required for optimal T cell activation. CTLA 4Ig inhibits skin APC and T cell interactions in vitro. Administration of CTLA 4Ig to patients with psoriasis vulgaris in a phase I trial produced a dose-dependent improvement in skin lesions. 7 of 11 patients in the top dosing groups achieved a 50% or greater decrease in psoriasis clinical scores. The use of CTLA4Ig in psoriasis patients provides a unique opportunity to ascertain the contribution of ongoing T-cell costimulation to the persistence of chronic cell-mediated inflammation in a human disease.Daclizumab and the chimeric basiliximab both monoclonal antibodies raised against CD25 , the humanized interleukin2 (IL-2) receptor on activated T-cell ,block normal IL-2 binding to this receptor and limit survival of activated T-cells by causing antibody—induced cell lysis. Nineteen patients with psoriasis in two centers received daclizumab at an initial dose of 2mg/kg, then 2mg/kg at weeks 2,4, 8 and 12. The result showed that a mean reduction in severity by 30% at 8 week after 4 weeks.HuMax-CD4 is a humanized anti -CD4IgG monoclonal antibody. A first double-blind phase of study indicated that this agent had a moderate effect on patients with the criteria of 750mg course. No side effect was found. Induce the destruction of CD45RO+DAB389IL-2 which is constructed by conjugating diphtheria toxin to soluble IL-2 is the first biological agent which began with early studies involving a fusion protein. This approach effectively targeted activated T-cells and improved psoriasis, but side effects of treatment including vascular leak syndrome, limited its application in cutaneous disease.Alefacept was designed to prevent the interaction between LFA-3 and CD2, interfering with the activation of T lymphocytes and modifying the inflammatory process. The first biologic agent for the treatment of moderate-to-severe chronic plaque psoriasis was approved by FDA in January 2003. A multicenter randomized, double-blind, parallel-group study concluded that treatment with alefacept 15mg IM provided highly significant improvements in all measures of psoriasis disease activity compared with placebo.Another humanized monoclonal antibody directed against CD2 , MEDI-507 (siplizumab) may produce prolonged clinical remissions and is currently ongoing in phase 2 studies. Blocking cytokinesInfliximab, the chimeric anti-TNF-a antibody tightly binds both soluble and membrane-bound forms of TNF-a and triggers complement-mediated lysis of TNF-a expressing cells. In controlled clinical trials, infliximab treatment has produced rapid and sustained improvements in psoriasis lesions and psoriatic joint involvement, with a favorable short-term safety and tolerability profile. Treatment with infliximab may be associated with an increased risk of infection or infusion reaction.Etanercept is a fusion protein comprising of two TNF- a receptors linked to IgGl and can bind only soluble TNF-a and TNF-p. Etanecept was approved by the FDA for treating moderate-to-severe plaque psoriasis and psoriatic arthritis in May 2004. In several well-controlled clinical trials, etanercept showed sustained efficacy in reducing the signs and symptoms of psoriasis in patients with moderate to severe disease. With the exception of injection site reactions, adverse event rates were similar to placebo and did not increase across higher doses.Adalimumab is a human recombinant immunoglobulinGl anti-TNF monoclonal antibody. It is useful in the treatment of psoriasis, psoriatic arthritis. The adverse effect profile seems to be comparable to that of etanercept. Causing immune deviationThe approaches of immune deviation exploit the competition between Thl and Th2 cytokines and their mutual down-regulation.Interleukin-8 is a chemotactic agent for neutrophils which contributes the processes of psoriasis. A fully human anti-IL-8 for the treatment of psoriasis had a moderate improment in high dose group( 1 .Omg/kg, 3.0mg/kg), meanwhile, there was mild side effects.Interleukin-10 and Interleukin-4 are both cytokines produced by Th2 cells which decrease in the pathogenesis of psoriasis. Clinical trials with IL-4^ IL-10 have yielded promising results although continuous treatments may be necessary in order to achieve sustained improvement in psoriasis.The potential therapeutic activity of a human monoclonal antibody to human interleukin-12P4o Subunit (anti-IL-12-P4o) has been established both in vitro and in vivo.An open-label study demonstrated significant and sustained concentration-dependment improvements in psoriatic lesions in most subjects.Above all, Biologic agents appear to act with greater target specificity than the systemic immunosuppressive drugs that are currently available and to offer a safe and effective alternative to conventional systemic therapies and photo-therapy for the treatment of moderate-to-severe chronic psoriasis. The biologies appear to be safer than traditional therapies, although long-term safety data still need to be established.