Current Drug Targets - Inflammation & Allergy - Volume 3, Issue 2, 2004

Psoriasis is a chronic inflammatory skin disease affecting 1-3% of the general population worldwide. Although in many patients the disease is mild and can be easily controlled with topical treatments, in about one third of cases the disease is severe with a high impact on patients' quality of life. Complex genetic predisposition and a variety of trigger factors are both important elements in disease expression and are presented in chapter 1 and 2. Psoriasis is an immune mediated disorder, with IFN-γ-producing type 1 T cells playing a fundamental role in disease pathogenesis, although the nature of the antigen towards which the immune response is directed remains elusive. Intrinsic, genetically-determined keratinocyte defects are also important to explain their abnormal behavior, and a number of mediators locally produced in the skin is involved in disease pathogenesis (chapter 3). Recently, a variety of biological agents targeting T cells or inflammatory cytokines have been proved to be very effective in the therapy of psoriasis (chapters 6, 9, 10 and 11). Indeed, psoriasis is serving as a very useful model for testing the ability of new biologicals to treat extracutaneous immune-mediated disorders. Moreover, a number of new drugs are under development with the objective of blocking T cell recruitment into the skin (chapters 7 and 8), or keratinocyte proliferation and cytokine production (chapters 12, 13 and 14).

The prevalence of psoriasis is relatively high in the general population, ranging between 0.6% and 4.8%, mainly as a result of chronicity and the absence of a cure. Although genetic-environmental interaction has been proposed as a model for the causation of psoriasis, the evidence for environmental factors is rather scarce. Risk factors, which have been documented in epidemiological studies include smoking, alcohol consumption, diet, infection, drugs, and stressful life events. Psoriasis affects the quality of life to substantial degree. Apart from a few cross-sectional surveys of large series of psoriatic patients, there have been no formal studies of the natural history and prognosis of established psoriasis. By imposing methodologic control and a numerate approach, epidemiology can offer a major contribution to understand psoriasis.

Psoriasis [OMIM*177900] is a common, chronic and papulosquamous inflammatory skin disease affecting approximately 2% of Caucasian. However, this disorder is rare among Japanese, Eskimos, West Africans and North American blacks and very uncommon in North American and South American natives. The causes for these variations are likely to be both genetic and environmental. Population-based studies and twin studies indicate that psoriasis is a heritable disease with a polygenic mode of inheritance with variable penetrance. Independent genome-wide scans have suggested the involvement of a large number of chromosomal regions (loci), and many candidate genes have been proposed. We discuss genetic approaches to the disease, results and interpretations of relevant studies, as well as future perspectives. Understanding the genetic basis of psoriasis will represent a major advance in our understanding of the disease and will reveal novel disease-specific biologic pathways.

Psoriasis is characterized by sustained T cell activation by antigen-presenting cells (APCs) in the lesions, and by a deviation of T cell differentiation to type 1 helper T and type 1 cytotoxic T cells, although no specific antigens have yet been determined. These characteristics are at least promoted by decreased IL-10 expression and the increased IL-12 expression observed in both the skin and stimulated peripheral blood mononuclear cells of psoriatic patients. Some of the cytokines produced by activated T cells are suspected to stimulate the proliferation of psoriatic keratinocytes. Among them, interferon-γ is the most likely candidate, although interferon-γ does not promote the growth of normal keratinocytes. In addition to the abnormal proliferation, psoriatic keratinocytes show abnormal differentiation and resistance to apoptosis. So far, however, it is still unknown whether these phenotypic and functional characteristics of psoriatic keratinocytes are only the consequences of the stimulation by activated T cells or are at least based on an inherent susceptibility. Recently, it has become clear that chemokines derived from activated keratinocytes or endothelial cells play a crucial role in recruiting T cells in the skin and inducing the neutrophilic infiltration that leads to the formation of subcorneal pustules (Munro's microabscess). Finally, recent developments in the detection and analysis of gene expression have revealed the molecules responsible for these steps. Some of them have become target molecules for the treatment of psoriasis. And indeed, it has become possible now to treat patients with new, innovative drugs.

Psoriasis is a complex disease with a spectrum of clinical manifestations. Psoriasis may express as a few coin-sized erythemato-squamous plaques up to widespread disease covering the entire body surface (erythrodermic psoriasis). Psoriasis may present as a few stable plaques or unstable disease, rapidly relapsing after treatment. Some patients may respond excellently to topical treatments whereas other patients may be difficult to manage, showing treatment resistance even to the systemic treatments. Therefore, a spectrum of treatments is available to individualize care of psoriasis. In this chapter the available treatments are presented. The vast majority of patients is treated with topical treatments, with vitamin D3 analogs and topical corticosteroids as the first line treatments. Tazarotene is an alternative for vitamin D3 treatment if this treatment fails. In some special cases, dithranol and tar treatment may be used. Phototherapy with UVB and photochemotherapy (PUVA) are indicated in patients not responding sufficiently to topical treatment. However, chronic exposure, in particular to photochemotherapy implies an increased risk for photo- carcinogenicity. Systemic treatments including methotrexate, cyclosporin, acitretin and fumarates are indicated in patients who cannot be managed with topical treatments or phototherapy, either for treatment resistance or cumulative toxicity. In this article the opportunities and limitations of the available treatments are presented.

Psoriasis is now accepted as a T-cell-mediated disease and that targeting of T cell function and / or trafficking is a logical approach to therapy. As a consequence of recombinant DNA technologies biologic therapies are synthesisable in sufficient quantities for clinical use. The original proof of concept for T-celltargeted therapies in psoriasis came with the demonstration that anti-CD4 monoclonal antibodies were effective. Progress is such that two T-cell-directed biologicals - alefacept and efalizumab - have recently been approved in the U.S.A. for the treatment of psoriasis. In addition to providing new therapies the T-cell-targeted biologicals with their selective approach can be used as sophisticated tools to dissect out and help our understanding of key pathomechanisms in psoriasis; the non - efficacy of anti - E-selectin is a case in point. It is likely that the most appropriate place for T-cell-directed biologicals in the management of chronic plaque psoriasis will be for maintenance, rather than induction, of remission. This is a reflection of mode of action and relative safety for long-term administration.

As leukocytes play a primary role in the immunopathogenesis of psoriasis, it is a reasonable assumption that preventing those cells from localizing to the sites of cutaneous inflammation can stop the disease process. Selectins, a family of three singlechain transmembrane adhesion molecules, which bind to carbohydrate moieties displayed on other cells, are pivotally involved in the initial steps of leukocyte recruitment, i.e. tethering and rolling along the endothelial lining of blood vessels. Thus, compounds impairing selectin functions have been developed to treat inflammatory disorders, such as psoriasis. Potential strategies to interfere with selectin functions include direct inhibition through monoclonal antibodies or small-molecule compounds, transcriptional regulation of selectin expression, and modulation of the post-transcriptional glycosylation of selectin ligands. More than a dozen different compounds targeting selectin functions are currently under development, several of which have shown promising effects on leukocyte recruitment and the therapy of inflammatory conditions under experimental conditions. However, based on preclinical and early clinical investigations, it appears that in some cases specifically targeting the function of single selectins may not be sufficient to effectively interrupt the inflammatory cascade. This is, at least in part, due to considerable redundancies and overlaps in the functions of the selectins, a notion that is corroborated by the apparently more pronounced therapeutic efficacy of some compounds with broader activity against several selectins. Overall, while targeting selectin functions promises rather selective and pathogenesis-based therapeutic approaches against psoriasis, the clinical value of such strategies, alone or in combination with other therapies, remains to be seen.

Chemokines are members of a superfamily of small, cytokine-like, chemotactic proteins that have recently been shown to critically regulate leukocyte trafficking. Accumulating evidence indicates that the chronically relapsing inflammatory skin disease psoriasis represents a T cell-mediated disease. Thus, the understanding of the underlying mechanisms of memory T cell homing to the skin may provide promising targets for the development of novel therapeutics. Here results of recent studies associating chemokines with a psoriatic phenotype and delineating their role in the recruitment of memory T cells to the skin are discussed.

Tumor necrosis factor-α (TNF-α) plays a fundamental role in the initiation and persistence of skin inflammation in psoriasis. The best evidence of the essential activity of this cytokine in the pathogenesis of psoriasis came from the observation that selective TNF-α blockers are dramatically effective in the therapy of this disease. The TNF-α inhibitors, infliximab and etanercept, have been employed with success in moderate to severe psoriasis and in psoriatic arthritis in randomized controlled trials. Anti-TNF-α biologicals induce rapid disease resolution and long-lasting remission, suggesting that they may alter the natural course of the disease. Further studies are warranted to more precisely establish the biological bases of the action of anti-TNF-α agents, better define which subgroup of patients can benefit most from this treatment, and the modalities of combination therapy with other antipsoriatic agents. Many other TNF-α inhibitors have been developed but none of them has been yet used in the therapy of psoriasis. Major limitations to the use of selective TNF-α blockers include the reactivation of latent tuberculosis, the risk of opportunistic infections, the development of specific antibodies, which is associated with a reduced duration of response to treatment, and the high cost.

Interleukin (IL)-10 is a pluripotent cytokine with effects on numerous cell populations, in particular circulating and resident immune cells as well as epithelial cells. With its potent immunoregulatory capacities its main biological function seems to be the limitation and termination of inflammatory responses. Thus its low level expression found in psoriasis may have pathophysiological relevance for this immune disease. Remarkably, induction of IL-10 expression was found by conventional antipsoriatic therapies, supporting the hypothesis that IL - 10 may be a key cytokine in psoriasis and that application of this cytokine itself may have therapeutic effects. In first clinical trials in patients with established psoriasis IL-10 showed moderate antipsoriatic effects and was well tolerated. Moreover, long term application in psoriatic patients remission showed that IL-10 therapy decreases the incidence of relapse and prolongs the disease free interval. The immunological effects observed during these clinical studies together with in vitro observations suggests that IL-10 exerts its antipsoriatic activity by effects on different cell populations including antigen presenting cells and T-cells (lasting type 1 / type 2 cytokine balance shift), but not trough direct effects on keratinocytes. In conclusion IL-10 seems to have major importance in psoriasis. Further investigations, in particular multicenter, placebo-controlled, double blind trials are required to fully determine whether IL-10 application will become a successful antipsoriatic therapy.

The experience with biologicals in currently available animal models suggest that inflammatory autoimmune disease depend on IFN-γ-producing T helper (Th) cells. Deletion of T cells improves most of these autoimmune diseases but bears the risks of general immunosuppression. Alternatively, selective deviation of the inflammatory, disease-inducing Th cells into an anti-inflammatory Th cell phenotype may be a promising strategy to treat inflammatory autoimmune diseases, such as psoriasis, rheumatoid arthritis, multiple sclerosis or autoimmune diabetes. The common feature of these organ-specific autoimmune diseases is the close association with IFN-γ-producing Th1 cells, which recognize organ-specific antigens and orchestrate the cells and mediators that ultimately cause the tissue damage. Even though the autoantigens recognized in psoriasis remain enigmatic, it has been the first Th1-mediated autoimmune disease successfully treated in humans by immune deviation. The basis of such an immune intervention therapy has been established in experimental mice with model diseases of multiple sclerosis, rheumatoid arthritis or autoimmune diabetes. In all these autoimmune diseases clinical improvement was associated with the skewing of IFN-γ producing autoantigenspecific Th1 cells into an IL-4 dominated Th2 phenotype. Such Th2 cells are still reactive to the autoantigen but provide a different cytokine pattern. The most powerful cytokines capable of inducing anti-inflammatory Th2 cells are IL-4 itself or IL-11. Interestingly, another agent that has been used for decades in the therapy of psoriasis in some European countries, fumaric acid esters (FAE), seems also to induce immune deviation. This review focuses on the potential immune deviating strategies based on the use of IL-4, IL-11 or FAE in the therapy of psoriasis, the effects of these agents on the immune system, potential risks and future perspectives for therapeutic intervention by immune deviation replacing immunosuppression.

Psoriasis is a common inflammatory and hyperproleferative skin disease characterized by infiltrated plaques of the skin and may involve nails, scalp and intertreginous areas. Recent years of research has shown that psoriasis can be treated topically with analogs of vitamin-D3. Impaired differentiation and increased proliferation of epidermal keratinocytes are key features in psoriatic lesions together with a local activation of T lymphocytes. Evidence has accumulated that analogs of vitamin D3 increase differentiation and inhibit proliferation of keratinocytes. Topical treatment with analogs of vitamin D3 have in a number of trials shown improvement of psoriasis. Vitamin D analogs show the same efficacy as potent topical corticosteroids and do not produce skin atrophy during long-term therapy. Vitamin D analogs can be used both as monotherapy and in combination with topical corticosteroids, UVB, PUVA, acitretin, methotrexate and cyclosporine. The vitamin D3 analog calcipotriol has been investigated in most detail and is available as an ointment, a cream and as a scalp solution. From clinical studies involving several thousands of patients, it can be concluded that calcipotriol is efficacious, safe and well-tolerated even on a long term basis.

While psoriasis is upon the age of biological treatments, additional researches have led to other new therapies for psoriasis, including targets aimed at nuclear receptors. PPARs are members of the nuclearhormone- receptor superfamily, including retinoid receptors and vitamin D receptors. Recent works have highlighted the role of PPARs, which transduce a wide variety of signals into a set of cellular responses at the level of gene transcription, as critical regulators of cutaneous homeostasis in regulating differentiation, proliferation, and inflammatory responses of the skin. PPAR agonists or antagonists may therefore, hold promise as interesting compounds for the treatment of various epidermal disorders characterized by inflammation, hyperproliferation and aberrant differentiation, such as psoriasis.

Psoriasis is recognised as a multifactorial disease with inflammatory, proliferative, angiogenic and genetic components contributing to the pathology. The disease, which may vary in intensity, remains clinically unmet although there have been several recent advances that have had a substantial impact on suffering. Histone deacetylase inhibitors represent a new class of therapeutic agent, initially developed for oncology, which prevent cell proliferation and induce differentiation. Here we discuss the possible application of HDAC inhibitors to psoriasis, focussing particularly on their anti-proliferative and anti-inflammatory activity. Our view, based upon the emerging clinical properties of HDAC inhibitors, reflects the growing recognition that HDAC inhibitors will be important therapeutic agents in diseases other than cancer.