Biologicals dramatic advances in the treatment of psoriasis

Innovations in biotechnology have made possible the development of several new systemic therapies for psoriasis - the "biologicals", a new group of compounds including monoclonal antibodies, fusion proteins and recombinant proteins. These novel biotechnological advances potentially offer designer drugs, which interfere with specific targets in the pathophysiological network of psoriasis and are thus much safer. The therapeutic strategy of biologicals is based on the knowledge derived from pathogenetic studies, which have focused on targeting disease relevant T-cell- or mediator-systems. Important targets include inactivation of soluble mediators such as tumor-necrosis-factor-alpha, the blockade of receptors for cytokines, adhesion molecules and the interference with T-cell activation by antigen-presenting cells. In addition, recombinant cytokines are able to modulate the immunological balance of this chronic inflammatory skin disease. Currently, up to forty agents are under investigation for the treatment of psoriasis. Four of these agents, alefacept, efalizumab, etanercept and infliximab have already impacted on routine clinical practice. Current developments in the treatment of psoriasis with biologicals are reviewed.     

Fulfilling an unmet need in psoriasis : do biologicals hold the key to improved tolerability?

Psoriasis is a chronic inflammatory disease of the skin affecting approximately 2% of the world's population. Traditional systemic treatments, including methotrexate, ciclosporin, psoralen plus UVA (PUVA), oral retinoids and fumaric acid esters, are widely used for severe disease and are effective in the short term. Severe psoriasis is a chronic disease and patients and physicians have expressed concerns about possible harm from organ toxicity, such as skin cancer (PUVA), hyperlipidaemia (retinoids), renal (ciclosporin) or hepatotoxicity (methotrexate). Long-term monitoring is required and may not detect early organ damage. The pathophysiology of psoriasis remains to be clarified, but advances toward the understanding of the immunological basis of psoriasis have uncovered the involvement of immunological pathways; for example, the role of tumour necrosis factor (TNF)-alpha, T cell proliferation and T cell activation, and migration to the epidermis. This advancement in knowledge combined with developments in recombinant technologies has led to the development of target-specific therapies. Biological agents are defined as proteins that can be extracted from animal tissue or produced via recombinant DNA technologies and possess pharmacological activity. Adalimumab, alefacept, infliximab, efalizumab and etanercept are examples of biological agents currently used for the treatment of psoriasis. Some of these are also therapy for other autoimmune conditions, such as rheumatoid arthritis and Crohn's disease. These biological agents are effective in psoriasis but raise new safety concerns. Information on the safety of biological agents in conditions such as rheumatoid arthritis and Crohn's disease can not be directly extrapolated to psoriasis. An increased incidence of lymphomas has been postulated to be associated with etanercept, infliximab and adalimumab; serious infections, such as tuberculosis, have also been reported with these three biologicals, all of which target TNF-alpha. Demyelinating disorders, such as multiple sclerosis, have been reported with some biologicals as has congestive heart failure. Alefacept, because of its mechanism of action of lowering the number of active T cells, is associated with low T cell counts. Efalizumab has been associated with thrombocytopenia and haemolytic anaemia. Data on the safety of >2.5 years' continuous treatment with efalizumab are reassuring and a valuable beginning to understanding the role and risk of harm of long-term therapy for a chronic disease. Longer follow-up studies and safety databases, for each of the biologicals used in psoriasis, are needed to ensure both prolonged efficacy and minimal risk of harm.     

T-cell-targeted biologicals for psoriasis

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-cell-targeted 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.     

A review of acitretin,a systemic retinoid for the treatment of psoriasis

Acitretin is a second-generation, systemic retinoid that has been approved for the treatment of psoriasis since 1997. It can be considered one of the treatments of choice for pustular and erythrodermic psoriasis. However, the efficacy of acitretin as a monotherapy for plaque psoriasis is less, although it is often used in combination therapy with other systemic psoriasis therapies, especially ultraviolet B or psoralen plus ultraviolet A phototherapy, to increase efficacy. Such combination treatments may potentially minimise toxicity by using lower doses of each of the two agents. All systemic retinoids are potent teratogens. The most common side effects are mucocutanous effects such as cheilitis and hair loss, which are dose-dependent. Acitretin is not immunosuppressive, is generally safe for long-term use and has no time limit restrictions, which makes it useful in combination therapy and for maintenance therapy.     

A review of acitretin, a systemic retinoid for the treatment of psoriasis

Acitretin is a second-generation, systemic retinoid that has been approved for the treatment of psoriasis since 1997. It can be considered one of the treatments of choice for pustular and erythrodermic psoriasis. However, the efficacy of acitretin as a monotherapy for plaque psoriasis is less, although it is often used in combination therapy with other systemic psoriasis therapies, especially ultraviolet B or psoralen plus ultraviolet A phototherapy, to increase efficacy. Such combination treatments may potentially minimise toxicity by using lower doses of each of the two agents. All systemic retinoids are potent teratogens. The most common side effects are mucocutanous effects such as cheilitis and hair loss, which are dose-dependent. Acitretin is not immunosuppressive, is generally safe for long-term use and has no time limit restrictions, which makes it useful in combination therapy and for maintenance therapy.     

Clinical monograph for drug formulary review: systemic agents for psoriasis/psoriatic arthritis

BACKGROUND: Significant advances in the pharmacologic treatment of psoriasis, most notably the introduction of the biologic agents efalizumab and alefacept, have occurred recently. In addition, another biologic agent, etanercept, was recently approved for the treatment of psoriasis and psoriatic arthritis, thus adding to the list of biologic agents approved for the treatment of these disease states. A review was conducted by the Drug Information Service of a pharmacy benefits manager (PBM) to determine the relative merits and place in therapy of commonly used systemic agents for the treatment of psoriasis and psoriatic arthritis. OBJECTIVE: To provide readers with a comprehensive clinical monograph on psoriasis and psoriatic arthritis agents, written with a managed care perspective, as used in actual drug formulary decision making by a PBM. METHODS: The drug formulary of this PBM is designed to provide health plans with an evidence-based review of drugs, therapeutic classes, and disease states with a managed care focus. For each therapeutic class or disease review, an extensive and thorough literature search of MEDLINE is conducted for efficacy, safety, effectiveness, and humanistic and economic data. Drug/disease-state databases (UpToDate online, MICROMEDEX), U.S. Food and Drug Administration clinical reviews, key Internet sites, medical/pharmacy-related news sites, clinical guidelines, and AMCP dossiers are also reviewed. Formulary drug monographs produced by the Drug Information Service of the PBM include a critical analysis and summary of disease-oriented and patient-oriented clinical outcomes, effectiveness, and humanistic data. Additional data considered and included in the formulary review process are clinical attributes, patent expirations/generic competition, off-label or pending indications, and pharmacoeconomic data. RESULTS: The biologic agents do not appear to be as efficacious as traditional systemic therapies but are associated with fewer long-term toxicities that often limit treatment duration with traditional systemic agents. Although no head-to-head comparisons between alefacept and efalizumab exist, efalizumab appears to offer slightly higher efficacy rates, while alefacept has a longer duration of action. Etanercept at the higher approved dose appears more efficacious compared with efalizumab or alefacept for the treatment of psoriasis, and it is the only biologic currently approved for the treatment of psoriatic arthritis. Efalizumab and alefacept are generally well tolerated, but rebound flare of psoriasis is associated with efalizumab, thus requiring continuous treatment to avoid a flare in disease. Efalizumab and etanercept can be self-administered by the patient, while alefacept and infliximab require administration by a health care professional. CONCLUSIONS: Systemic therapy is reserved for patients with moderate-to-severe psoriasis or patients with psoriatic arthritis. The biologic agents are not as efficacious as traditional therapies but, due to better tolerability, are gaining acceptance in the treatment of psoriasis and psoriatic arthritis. The biologic agents differ in efficacy rates and are generally well tolerated. Clinical attributes, overall efficacy, and economic costs associated with the biologic agents will be significant factors in selecting agents for the treatment of psoriasis and psoriatic arthritis.     

Targeting tumor necrosis factor-alpha in the therapy of psoriasis

Tumor necrosis factor-alpha (TNF-alpha) 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-alpha blockers are dramatically effective in the therapy of this disease. The TNF-alpha inhibitors, infliximab and etanercept, have been employed with success in moderate to severe psoriasis and in psoriatic arthritis in randomized controlled trials. Anti-TNF-alpha 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-alpha 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-alpha 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-alpha 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.     

Renal cell carcinoma therapy: Current and new drug candidates

Renal cell carcinoma (RCC) is the most common and lethal tumor of the urological system. Curative treatment of localized RCC includes nephrectomy, radio-ablation, and active surveillance, whereas metastatic RCC (mRCC) requires a combination of surgery and systemic therapy. Response to conventional therapy is limited but, recently, many novel therapies for mRCC have emerged, including targeted therapies and new immunotherapeutic agents. Nevertheless, development of resistance and limited durable responses demand new anticancer candidates with improved selectivity and efficacy. In this review, we summarize recent preclinical studies of novel natural and synthetic compounds to treat RCC, detailing their mechanisms of action and anticancer activities.     

A review of acitretin for the treatment of psoriasis

Background: Acitretin is an oral retinoid that is approved for the treatment of psoriasis. It is unique compared to other systemic therapies for psoriasis such as methotrexate and cyclosporine in that it is not immunosuppressive. It is, therefore, safe for use in psoriasis patients with a history of chronic infection such as HIV, hepatitis B, hepatitis C or malignancy who have a contraindication to systemic immunosuppressive therapy and require systemic therapy because topical therapy is inadequate and they are unable to commit to phototherapy. Acitretin is one of the treatments of choice for pustular psoriasis. Even though acitretin is less effective as a monotherapy for chronic plaque psoriasis, combination therapy with other agents, especially UVB or psoralen plus UVA phototherapy, can enhance efficacy. Objective: To provide an updated review of the safety and efficacy of acitretin in the treatment for psoriasis. Methods: Literature review of journal articles from 2008 to 2009 since the last review of acitretin evaluated medical literature from 2005 to 2008. Results/conclusion: Acitretin is an effective systemic therapy for psoriasis and is generally well tolerated at low doses for long-term use. If monotherapy with acitretin is inadequate, it can be used in combination with other treatments, particularly UVB phototherapy, to increase efficacy.     

Safety considerations with combination therapies for psoriasis

ABSTRACT

Introduction: Psoriasis is a chronic inflammatory skin disease that waxes and wanes, and long-term remission can be difficult to achieve regardless of disease severity. Currently, numerous treatment options are available for psoriasis including steroid and non-steroid topical agents, phototherapy, oral systemic agents, and biologics, with many more therapeutic agents under development.

Areas covered: This article will review various combination therapy strategies such as rotational therapy and sequential therapy and describe a variety of safe and effective combination therapies for the treatment of psoriasis. Two or more agents with different mechanisms of action and safety profiles can be used to achieve and/or maintain adequate disease control while minimizing the toxicity of treatments. Combination therapy can also be used when a single agent is not enough for treating recalcitrant disease. Choosing a combination regimen that maximizes safety and efficacy while considering patient usability and compliance can be a challenge.

Expert opinion: Given the various treatment options currently available for psoriasis and more agents under development, combination therapy will continue to be a valuable treatment strategy for any patient with psoriasis. It is crucial for clinicians to carefully consider the fine balance between safety and efficacy when combining various therapeutic agents.     

Medical backgrounder: psoriasis

Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European populations. Psoriatic lesions are extremely characteristic of the disease, which allows for simple diagnosis. A clear understanding of the pathogenesis of psoriasis does not yet exist. Hyperproliferation of keratinocytes is a further characteristic feature. Studies have depicted that the epidermal cell cycle of psoriatic lesions is shortened by approximately eight-fold more than normal. The lesions are classified as erythrosquamous, due to the erythema which develops asa result of involvement of the vasculature, and the involvement of the epidermis with scale formation. The diagnosis of psoriasis can usually be established on clinical grounds. If the clinician is in doubt, a small cutaneous punch biopsy and subsequent histopathological examination can be performed. There are multiple therapeutic options for psoriasis. First-line therapy for patients with moderate to severe psoriasis is the application of topical agents, followed by phototherapy (UVB) for more extensive disease. If extensive disease does not respond to UVB, second-line agents include psoralen plus UVA (PUVA), methotrexate, cyclosporine or other systemic agents, including novel biologic therapies. New psoriasis treatment regimens have been developed and include combination, rotational and sequential therapy.     

Advancements in the treatment of psoriasis: role of biologic agents

OBJECTIVE: To evaluate the role of biologic agents as antipsoriatic therapy. SUMMARY: Mild psoriasis can generally be managed with topical therapy. Moderate-to-severe psoriasis has traditionally been treated with systemic therapies such as cyclosporine, methotrexate, retinoids, and phototherapy (ultraviolet B, psoralen plus ultraviolet A). The treatments for moderate-to-severe psoriasis often do not meet patient and physician expectations because of significant side effects (e.g., organ toxicity, skin cancer), lack of durable efficacy, and inconvenient administration schedules (e.g., daily dosing, multiple weekly exposures). The recognition of psoriasis as a T-cell.mediated disease has led to the development of biologic agents that more specifically target key steps in the pathologic process. A review of the literature was conducted to identify randomized controlled trials that have been published on the efficacy, safety, and quality-of-life effects of both approved and investigational biologics for the treatment of psoriasis. The first 2 biologic agents for the treatment of moderate-to-severe chronic plaque psoriasis were approved by the U.S. Food and Drug Administration (FDA) in 2003, alefacept in January and efalizumab in October. Both agents have demonstrated favorable safety profiles in clinical trials and significant benefits on patient quality of life. Head-to-head trials are lacking, but in placebo controlled trials, similar percentages of patients appear to respond to each of these 2 drugs. An advantage of alefacept is that it has been shown in clinical trials to provide durable off-treatment efficacy (approximately 7 months). Efalizumab has a relatively quick onset of antipsoriatic effect, but it needs to be administered once weekly continuously to maintain symptom control. Etanercept (approved by the FDA for treating moderate-to-severe plaque psoriasis in May 2004) and infliximab (not FDA-approved for psoriasis treatment) have also shown promise in randomized controlled trials, although less data are available on these agents. Case reports and pilot studies suggest that other biologics under investigation may also prove useful for the treatment of psoriasis. Patient populations that may particularly benefit from biologic therapy are discussed. CONCLUSION: Biologic agents appear to offer a safe and effective alternative to conventional systemic therapies and phototherapy for the treatment of moderate-to-severe chronic plaque psoriasis. The biologics appear to be safer than traditional therapies, although long-term safety data still need to be established.     

Recent patents and new strategies in the treatment of psoriasis

Several systemic drugs are available for the treatment of moderate-to-severe plaque psoriasis, including photochemotherapy, retinoids, cyclosporin, methotrexate, and fumarates. Although these options have been shown to maintain efficacy, frequently they produce significant subjective side effects. Recently, there has been a significant advance in developing newer medications that may be used for psoriasis. The progress in laboratory techniques has improved our understanding of the immuno-pathogenesis of psoriasis to a point where a number of key cytokines and immune cells--notably tumor necrosis factor-alpha (TNF-alpha) and T-cells respectively have been identified as critical factors contributing to the immuno-pathogenesis of the disease. Many of these medications are termed "biologic response modifiers" or, more commonly, "biologicals". The latter are a set of different engineered proteins designed to modify defined patho-physiological pathways that regulate pivotal immunological processes such as lymphocytes activation and cytokines production. New strategies and new formulation of biologic therapies, angiogenesis inhibition, immunomodulatory compounds, intracellular messenger targets, are of current interest to dermatologists and medicinal chemists. This review summarizes the current understanding of the immuno-pathogenesis of psoriasis, the mechanism of action and efficacy of current biologic therapies, new patents and their possible future applications in the treatment of psoriasis.     

Emerging topical treatments for psoriasis

Introduction: Psoriasis is an immune-mediated chronic inflammatory skin disease which classically presents as erythematous, scaly plaques affecting extensor surfaces of the limbs, scalp and trunk. Approximately 80% of patients have a mild-to-moderate form routinely treated with topical medications, whereas phototherapy, systemic and biological therapies are typically reserved for treatment of moderate-to-severe psoriasis.

Areas covered: The major advances in psoriasis therapy in the past 15 years have been in new immunomodulatory and biological molecules, with a significant unmet need to have new, efficient and safe topical treatment options for the large percentage of patients for whom systemic therapy is not indicated. The available topical therapies (corticosteroids and vitamin D3 analogs) have remained relatively unchanged over the past several decades. This article reviews emerging topical drugs and formulations currently under evaluation in clinical trials.

Expert opinion: The time is right for a revolution in our topical therapy armamentarium. It has lagged significantly behind the systemic biological evolution of new drug development. Our large psoriasis population with mild-to-moderate psoriasis certainly deserves potent but safe and innovative topical agents with a new mode of action as well as with long-lasting clinical efficacy.     

Use of retinoids in the treatment of psoriasis

The limitations of conventional therapy for psoriasis are reviewed, and the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosing and therapeutic monitoring of etretinate and other retinoids are described. Traditional treatments for psoriasis include topical application of anthralin and coal tar ointments; systemic therapy with corticosteroids or methotrexate; and systemic or methotrexate; and systemic psoralens combined with exposure to ultraviolet light (PUVA). The topical therapies are beneficial but aesthetically displeasing to patients; the systemic treatments are associated with severe adverse reactions. Etretinate provides another option in the treatment of psoriasis. Etretinate and acitretin, an investigational retinoid, appear to be effective oral therapies for severe variants of psoriasis, especially pustular psoriasis. Retinoids generally do not offer substantial therapeutic advantages over other treatments for chronic-plaque psoriasis. The most common adverse effects of etretinate are cheilitis, alopecia, desquamation of the skin, drying of mucous membranes, and pruritus. Use of low-dose etretinae in combination with other forms of therapy, such as corticosteroids or PUVA, may minimize the frequency of adverse effects. Etretinate is a known teratogen. Its elimination half-life is prolonged to 100-120 days with long-term use. Acitretin, the carboxylic acid derivative of etretinate, has a much shorter elimination half-life than etretinate (50 hours after multiple doses). Its adverse-effect profile is similar to that of etretinate. Etretinate and acitretin appear to be clinically effective for therapy of severe variants of psoriasis. Etretinate should not be used to treat mild psoriasis because of the high incidence of serious adverse effects.     

银屑病的免疫生物学疗法

银屑病是一种慢性T细胞介导的炎性和增殖性皮肤病,近年来有关银屑病的治疗一直是个令人困惑的问题。随着银屑病免疫病理机制研究的不断深入及基因工程技术的突飞猛进,已研制或正在研制一批生物制剂,包括融合蛋白、单克隆抗体、重组细胞因子等。这些生物制剂具有靶向特异性、疗效确切、毒副作用少,为中、重度银屑病治疗提供了新的方向。现就近年来银屑病的生物学疗法及其进展进行综述。     

Novel biological immunotherapies for psoriasis

Psoriasis is a common skin disease affecting 1 - 3% of the white population. Although its physiopathogenesis still remains poorly understood, recent data suggest a key role played by memory T cells in the genesis of skin and joint lesions. Recent developments in the understanding of cellular mechanisms underlying psoriasis and in biotechnologies have given rise to a generation of biological agents that have shown clinical efficacy in treating psoriasis. These agents, including chimeric antibodies, fusion proteins and recombinant interleukins, specifically target the activated memory T cells directly involved in the development of psoriasis lesions and inhibit their action either directly or through inhibition of pro-inflammatory cytokines. Compared with conventional systemic treatments, they show a better safety profile and allow durable remissions. Some of these agents were very recently marketed for the treatment of psoriasis and hopefully others will follow. These biologicals have opened a new era for the management of this disease; they are reviewed in this article, based on data available in the literature.     

Novel biological immunotherapies for psoriasis

Psoriasis is a common skin disease affecting 1 – 3% of the white population. Although its physiopathogenesis still remains poorly understood, recent data suggest a key role played by memory T cells in the genesis of skin and joint lesions. Recent developments in the understanding of cellular mechanisms underlying psoriasis and in biotechnologies have given rise to a generation of biological agents that have shown clinical efficacy in treating psoriasis. These agents, including chimeric antibodies, fusion proteins and recombinant interleukins, specifically target the activated memory T cells directly involved in the development of psoriasis lesions and inhibit their action either directly or through inhibition of pro-inflammatory cytokines. Compared with conventional systemic treatments, they show a better safety profile and allow durable remissions. Some of these agents were very recently marketed for the treatment of psoriasis and hopefully others will follow. These biologicals have opened a new era for the management of this disease; they are reviewed in this article, based on data available in the literature.     

Disease and treatment burden of psoriasis: examining the impact of biologics

Plaque psoriasis is a chronic, inflammatory skin disease that can be difficult to treat. Traditional systemic agents, topical agents, phototherapy and biologic therapies can be used for patients with psoriasis. The authors reviewed published results from a variety of sources in order to better understand the effects of psoriasis treatments on patient satisfaction, patient adherence, healthcare resource utilization and productivity. Patients with psoriasis consider many factors when evaluating therapies, including the time for the therapy to be effective, cosmetic issues common with topical therapies and travel to and from phototherapy centers. Satisfaction with and adherence to biologic therapies appears to be greater than for traditional therapies. Although biologic therapies are generally more expensive than are traditional, these agents may contribute to decreased healthcare utilization and increased productivity.     

Current investigational drugs in psoriasis

INTRODUCTION: The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data. AREAS COVERED: This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available. EXPERT OPINION: Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.