Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry - Volume 6, Issue 3, 2007

Biologic agents are becoming more important in dermatology in recent years due to their success in treating some skin diseases resistant to other medical therapies. In a few studies, they have been found effective in increasing the quality of life of psoriatic patients by removing the physical and social restrictions of the disease. Though costly and difficult to prescribe, they are used more in dermatology as other rheumatic diseases. In this issue, after a brief introduction of biologic drugs used in dermatology, their mechanism of action, dermatologic indications and side effects will be discussed. Also, the advantages and disadvantages of different biologic drugs will be compared in light of recent literature. New indications for use as well as the side effects of these drugs will lead us to consider the extent of their usage in this field. As far as possible, the authors of this issue have collected recent data from several random controlled studies. I hope this review will guide readers in the appropriate use of biologics and answer most questions concerning these new agents.

In recent years, the role of T cells, dentritic antigen presenting cells (APCs) and cytokine network in inflammatory dermatoses has been more completely understood. This in turn has enabled the completion of new potentials and goals in immunotherapy. As research in Immunodermatology increased, newly targeted treatments for immunodisfunction were also developed. These treatments were not only beneficial for the patient, but also created experimental tools for better understanding disease pathophysiology and for rethinking nosology. In Dermatology, especially psoriasis treatment, targeted biologic treatment methods have been developed. Immunobiologic treatments can be defined by the therapeutic agents produced by the organisms by using recombination biotechnology. This article will briefly discuss the general characteristics of immunobiologic agents.

Inhibition of the proinflammatory cytokine TNF-α has been shown to be an effective strategy for treating inflammatory dermatoses. Etanercept competitively inhibits the interaction of TNF, interrupting the proinflammatory cytokine cascade and preventing TNF mediated cellular responses. The success of etanercept in a wide range of dermatologic conditions especially in psoriasis gives a new hope in dermatological therapy field. This article reviews the pharmacokinetic properties, safety profile, administration route and efficacy in different dermatological conditions of etanercept.

Infliximab is a chimeric monoclonal antibody that binds to tumor necrosis factor-alpha (TNF-α) which is major cytokine playing pivotal role in inflammatory diseases. Efficacy and safety of infliximab was studied in numerous inflammatory skin diseases where TNF-α is involved in pathogenesis especially in psoriasis and psoriatic arthritis. This review summarizes the current data revealing the efficacy and safety of infliximab in treating various dermatoses beyond its approved indications. Results of clinical trials and case reports suggest that infliximab is a promising agent in treating inflammatory cutaneous dermatoses where conventional therapies fail to respond or have limited effect due to potential side effects.

Efalizumab is a recombinant humanized monoclonal antibody designed to selectively and reversibly block the activation, reactivation and trafficking of T-cells that lead to the development of psoriasis. It has been approved in the US in 2003 and in Europe in 2004 for the treatment of adults with moderate to severe chronic plaque psoriasis for whom other systemic treatments or phototherapy have been inadequate or inappropriate. The currently suggested dose of 1mg/kg/wk has been shown to have significant therapeutic effect on psoriasis in several controlled trials. Efalizumab has a favorable safety and tolerability profile and provides dermatologists with a effective and safe treatment alternative. The solution to the conflict which is between the currently high cost of this drug and its suggested continuous use for long-term psoriasis control will dictate the future of efalizumab.

Alefacept is a fully human fusion protein, being the first biologic agent approved for the treatment of chronic, moderate to severe plaque-type psoriasis. Its dual mechanism of action involves inhibition of T-cell activation and selective reduction of memory T cells. It has a slow onset of action, peaking approximately 18 weeks after the first injection. However, it is associated with long remissions without the need for maintenance therapy in psoriatic patients and its efficacy improves with subsequent courses with a high safety profile. The mechanism of action, the results of the clinical trials, its efficacy, pharmacodynamic effects on circulating lymphocytes, and safety and tolerability of alefacept are summarized in this review. Current treatment guidelines are also presented.

Patients with moderate-to-severe psoriasis, will require phototherapy, systemic therapy, or both for adequate disease control. Although a number of well established therapies are available for psoriasis, there are still unmet needs remain, such as longterm safety and practicability. Psoriasis currently regarded as an immune-mediated inflammatory disease, inflammatory response is amplified as a result of increased tumor necrosis factor (TNF) α expression in psoriatic plaques. New biological agents targeting TNFα are promising in psoriasis therapy. Adalimumab is an fully human recombinant IgG 1 monoclonal antibody specific for human TNF α that has been approved for the treatment of rheumatoid arthritis. Adalimumab has only recently been introduced to dermatology. Given the known pathophysiologic role of TNF in psoriasis, this brief review aimed to evaluate the efficacy and safety of adalimumab in the treatment of psoriasis and other dermatoses which it found off-label uses.

Imiquimod is an immune response-modifying agent that demonstrates potent antiviral and antitumour activity. Although it's use has been approved by the FDA (Food and Drug Administration) in the treatment of external genital and perianal warts, actinic keratosis on the face or scalp and superficial basal cell carcinomas, it has recently been tried to treat different types of dermatological diseases including molluscum contagiosum, herpes simplex, melanoma, T-cell lymphoma. Side effects of imiquimod are erythema, itching, burning, crusting, and rarely cytokine-release syndrome, exacerbation of inflammatory skin conditions. In this review, the structure of imiquimod, mechanism of action and its usage in the treatment of different skin diseases are discussed.

Pimecrolimus and tacrolimus represent the first members of a new class of medications, calcineurin inhibitors. These topical macrolide immunomodulators have been successfully introduced in the treatment of atopic dermatitis. They inhibit T cell proliferation, mast cell degranulation, production and release of IL-2, IL-4, IF-γ and TNF-α. They do not effect endothelial cells and fibroblasts, so they do not induce skin atrophy. In several studies, it has been shown that topical pimecrolimus and tacrolimus are effective, well tolerated and safe in both adults and children with atopic dermatitis. Pimecrolimus permeates less through the skin than tacrolimus and much less than corticosteroids. It has a lower potential for transcutaneous absorption resulting in a lower risk of systemic effects. In addition, they have been used in other inflammatory skin diseases including psoriasis, lichen planus, seborrheic dermatitis, allergic contact dermatitis, vitiligo, pyoderma gangrenosum, alopecia areata, graft versus host disease, akne rosacea, etc. In this review article mechanism of action, efficacy, safety of pimecrolimus and tacrolimus, and future directions of these immunomodulators were discussed.

The members of the S100 protein family compose a multigenic family of non-ubiquitous cytoplasmic Ca2+- binding proteins of EF-hand type that are differentially expressed in a wide variety of cell types. In particular, S100A8 and S100A9 also known as calgranulins are abundant in myeloid cells. Profound expression of S100A8 and S100A9 has been reported in various disorders, such as rheumatoid arthritis, inflammatory bowel disease and vasculitis. Thus, the S100/calgranulins are associated with inflammatory disorders as they are secreted from phagocytes upon cellular activation and track disease activity. In addition to their abundance in myeloid cells S100A8 and S100A9 can also be found in the epidermis upon response to stress. S100A8 and S100A9 form heteromeric protein complexes that are located in the cytosol of resting phagocytes and that can exhibit two independent translocation pathways upon cellular activation. Therefore, it has been assumed that membrane- associated and soluble S100A8/A9 may have distinct cellular functions. Recent data indicate that intracellular S100A8/A9 might be involved in the (phagocyte) NADPH oxidase activation, whereas the secreted form exerts antimicrobial properties and induces apoptotic and cytotoxic activities. The S100 proteins are suggested to bind to the receptor for advanced glycation end products (RAGE), and the RAGE/S100 interaction has been considered to represent a novel proinflammatory axis involved in several inflammatory diseases, thereby offering an attractive model to explain how RAGE and its proinflammatory ligands contribute to the pathophysiology of several inflammatory diseases. This review addresses recent developments regarding the functional role of the two S100 proteins in inflammation. In view of the current knowledge the author will show that these S100-proteins are reliable clinical parameters as well as attractive targets to modulate inflammation.