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... Currently approved α4 integrin antagonist, natalizumab, is at high risk of developing PML. 590 Efalizumab, an αLβ2 integrin antagonist previously approved for the treatment of plaque psoriasis, 591,592 was also withdrawn from the market due to the incidence of PML. 593 A restricted risk management plan is necessary to help reduce the potential risk of PML in clinical practice and clinical trials. ...
Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.
... Anti-trafficking agents used in the treatment of immune-mediated inflammatory diseases Efficacy proved in phase III55,177 , but no or limited approval owing to cases of PMLAJM300Small molecule (antagonist) Ulcerative colitis III Primary end point met 170 label pilot study completed178 , not further developed owing to cases of PML Psoriasis Efficacy proved in phase III143 , but approval retracted owing to cases of PML Induction: primary end point met in two of three trials; maintenance: primary end point not met; comparable effects to infliximab[157][158][159][160] Crohn's disease II Primary end point not met167 ...
Immune cell trafficking is a complex and tightly regulated process that is indispensable for the body's fight against pathogens. However, it is also increasingly acknowledged that dysregulation of cell trafficking contributes to the pathogenesis of immune-mediated inflammatory diseases (IMIDs) in gastroenterology and hepatology, such as inflammatory bowel disease and primary sclerosing cholangitis. Moreover, altered cell trafficking has also been implicated as a crucial step in the immunopathogenesis of other IMIDs, such as rheumatoid arthritis and multiple sclerosis. Over the past few years, a central role of the gut in mediating these disorders has progressively emerged, and the partly microbiota-driven imprinting of particular cell trafficking phenotypes in the intestine seems to be crucially involved. Therefore, this Review highlights achievements in understanding immune cell trafficking to, within and from the intestine and delineates its consequences for immune-mediated pathology along the gut-liver, gut-joint and gut-brain axes. We also discuss implications for current and future therapeutic approaches that specifically interfere with homing, retention, egress and recirculation of immune cells.
... The authors found that efalizumab was superior to placebo on all end points. PASI 75 was achieved in 27% of patients treated with efalizumab and only 4% of patients in the placebo group [20]. ...
Psoriasis is a chronic, immune mediated disorder affecting approximately 2% of the population. Even in our days, patients with psoriasis are confronted with stigmatization and social rejection. As a result, their quality of life is significantly impaired. Biological therapies have revolutionized the treatment of moderate to severe psoriasis. The aim of this paper is to look over the most important biological therapies available for the management of plaque-type psoriasis.
... Measuring tissue responses is especially important in AD compared to psoriasis, given the strong placebo effect commonly encountered in clinical trials of AD therapeutics. Unlike a placebo response of 3% in psoriasis [11,123,[126][127][128][129][130], placebo responses in clinical trials for AD range between 15% and 23%, which can lead to difficulty in identifying significant responses [12,131]. Monitoring molecular responses to treatment provides an early measure of efficacy compared to the clinical response, and provides an important basis for comparison in AD trials. ...
... Although there have been only a few published antiadhesion molecule RA clinical trials without much success (see below), there have been some successes in the targeting of adhesion molecules for the treatment of other autoimmune conditions. Thus, efalizumab, a humanized IgG 1 monoclonal antibody against the CD11a chain of LFA-1 significantly improved clinical endpoints in a phase III clinical trial in patients with severe plaque psoriasis [177] and alefecept, a soluble LFA-3 fusion protein was shown to have proven efficacy in patients with chronic plaque psoriasis in which LFA-1 blockade resulted in clinical remission and an increase in time between the need for additional drug therapy [178]. In an ulcerative colitis clinical trial, a monoclonal antibody reactive with 47 integrin, namely, MLN02 improved the ulcerative colitis clinical score and endoscopic remission criteria [179]. ...
The therapy of rheumatoid arthritis (RA) was revolutionized by basic research studies and biopharmaceutical development of the first generation of anti-rheumatic biologic agents (i.e. biological response modifiers), which targeted the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). Further studies resulted in biological response modifiers that have also targeted activated T- and B-lymphocytes both of which play a prominent role in RA pathogenesis and disease progression. Despite the relatively impressive RA diseasemodifying effects of these biologic agents during the post-FDA approval period, there are reports of moderate to severe adverse events associated with their continuous use. Additionally, there is accumulating evidence indicating that antirheumatic biologic agents, while dampening RA disease activity as measured by the American College of Rheumatology (ACR) criteria in clinical trials or other arthritis disease activity instruments employed in studies after approval of these anti-rheumatic medicines by the FDA do not entirely halt the erosive joint cartilage and bone destruction characteristic of RA. There is also still some uncertainty as to how long the available anti-rheumatic biologics can be continuously employed as RA therapies. Since the development of TNF-α/IL-1/IL-6 anti-rheumatic biologics, several additional cytokines with pro-inflammatory activity as well as their receptors, which initiate upstream pathophysiologic effects, have been identified and characterized. In several cases, these cytokines have been cloned and sequenced. Thus, cytokines, such as IL-7, IL12/IL-23, IL-15, IL-16, IL-17/IL-18, IL-19/IL-20/IL-22 and IL-32, have been implicated in arthritis development in animal models of RA and measurements in synovial tissue and synovial fluid obtained from patients with RA also suggested a role for them in RA disease progression, if not in its pathogenesis. There has also been compelling evidence that cytokines with chemokine-activity and adhesion molecules also play a crucial role in RA via their capacity to recruit and retain leukocytes, macrophages, monocytes and endothelial-cell complexes in RA synovial joints. Taken together, non-TNF-α/non-IL-1/non-IL-6 cytokines, chemokines and their receptors as well as adhesion molecules appear to be worthwhile targets for drug development in RA.
... Efalizumab (Raptiva) is a humanized monoclonal antibody that blocks interactions between T-cell-associated CD11a/LFA-1 and ICAM-1 on antigen presenting cells, as well as T cell activation and trafficking to skin. In a clinical trial with this drug, PASI-75, as well as a decreased number of lesional T cells and reduced epidermal thickness, were seen in 27% of patients compared with only 4% of patients that received placebo (Gordon et al., 2003). However, after discontinuation of efalizumab, up to 14% of patients had a dramatic worsening of psoriasis (Carey et al., 2006). ...
Psoriasis vulgaris is a chronic, debilitating skin disease that affects millions of people worldwide. There is no mouse model that accurately reproduces all facets of the disease, but the accessibility of skin tissue from patients has facilitated the elucidation of many pathways involved in the pathogenesis of psoriasis and highlighted the importance of the immune system in the disease. The pathophysiological relevance of these findings has been supported by genetic studies that identified polymorphisms in genes associated with NFκB activation, IL-23 signaling and T helper 17 (Th17)-cell adaptive immune responses, and in genes associated with the epidermal barrier. Recently developed biologic agents that selectively target specific components of the immune system are highly effective for treating psoriasis. In particular, emerging therapeutics are focused on targeting the IL-23-Th17-cell axis, and several agents that block IL-17 signaling have shown promising results in early-phase clinical trials. This review discusses lessons learned about the pathogenesis of psoriasis from mouse-and patient-based studies, emphasizing how the outcomes of clinical trials with T-cell-targeted and cytokine-blocking therapies have clarified our understanding of the disease.
Background: Psoriatic disease (PsD) is a complex systemic disorder with cutaneous and musculoskeletal (MSK) manifestations. Current evidence on pharmacological interventions –effective Across-The-Spectrum-Of-Clinical-Manifestations (ATSOCM) of early, systemic treatment-naïve PsD- is limited. This review aims to appraise such evidence.
Methods: This systematic review examined seven Patient-Intervention-Comparator-Outcome (PICO) research questions to address the interventions’ efficacy on: ATSOCM PsD activity; peripheral arthritis; dactylitis; spondylitis; enthesitis; skin; and nails. Early PsD was defined as a disease duration of ≤2 years, except for studies investigating outcomes restricted to the skin. Eligible references were clinical trials or well-designed prospective studies/series reporting on: adult humans, untreated, with cutaneous and/or MSK features of PsD.
Results: Nine references (out of 160 319, publication range 1946–2019) fulfilled the eligibility criteria. No study adopted comprehensive (that is, simultaneous assessment of different PsD manifestations) composite indices as primary outcome measures. Individual studies reported that apremilast and biologics successfully improved outcomes (DAPSA, MDA, PASDAS, PASI, PsARC) when efficacy analyses were restricted to single manifestations of untreated PsD. Only qualitative synthesis of evidence was possible, due to: a) data heterogeneity (disease classification criteria, outcome measures); b) unavailable data subsets -focused on early, untreated PsD- at single study level; c) insufficient data on the participants’ exposure to previous treatment.
Conclusions: Effective interventions –albeit limited in scope- for early, treatment-naïve PsD were found. No study provided evidence about the management of co-occurring cutaneous and MSK manifestations in early, treatment-naïve PsD. This review highlighted an unmet need in research on early PsD.
This chronicle of psoriasis begins in ancient times when psoriasis, leprosy, and other inflammatory skin disorders were thought to be the same condition. The identification of psoriasis as a distinct entity did not occur until the nineteenth century, when clinical descriptions distinguished it from other cutaneous disorders. Histopathologic descriptions in the 1960s and 1970s shed some light on the pathophysiology of psoriasis, but many aspects of the disease remain unknown to this day.
Novel and innovative treatment options for atopic dermatitis are underway. The recent advancements in understanding atopic dermatitis are reminiscent of the progress made in psoriasis research over a decade ago.
It is possible to suggest that the past two decades have led to greater advances in the treatment of extensive psoriasis than almost any other disease. The number of treatments available has grown tremendously and our treatment goals have changed radically. While at the turn of the century it was thought that complete clearance of psoriasis in patients who had extensive disease was not feasible in almost any patient, we now have medications that can attain complete clearance in up to 40 % of patients. With achievement of higher levels of response, a new understanding of the benefit of these responses to patients has identified a need for greater responses.
The development of targeted biologic immunotherapy for psoriasis has historically relied on the understanding of the pathophysiology of disease. However, the targeted nature of these medications, in concert with fortuitous clinical observation, has furthered the understanding of the pathological mechanisms in psoriasis. In turn, new insight has led to even more effective treatments. Thus, the use and study of biologics improves disease treatment in two ways. Their targeted nature can promote individual health by helping to treat the patient’s disease while their study leads to global benefit by directing the creation of newer treatments. In this chapter, we will examine how biologics have changed our understanding of psoriasis and has led to the development of a multitude of new and exciting treatments.
The importance of T-cell activation, T-cell migration into the dermis, and the production of pro-inflammatory molecules has been shown to be key steps in the pathogenesis of psoriasis. Targeted immunosuppressive agents that interfere with initial T-cell activation were some of the initial biologic agents introduced for the treatment of moderate-to-severe psoriasis. Two such agents are alefacept and efalizumab. These agents demonstrated moderate efficacy in the treatment of psoriasis. In 2009 the manufacturer of efalizumab voluntarily withdrew efalizumab from the market due to its association with an increased risk of progressive multifocal leukoencephalopathy. In 2011 the manufacturer of alefacept also withdrew the drug from the market, although due to business needs not due to a re-assessment of safety or efficacy. The future of T-cell targeted therapy remains uncertain as new biological agents targeting other components of the immune response are being developed.
An understanding of disease overall and, skin disease in particular, has been a unique part of modern times. Previously those with psoriasis were often mislabeled, poorly regarded, and suffered as a consequence. Symptoms were often considered the disease itself; this lack of understanding made for difficulty in establishing psoriasis as a disease entity. The subsequent struggle to understand the pathogenesis of psoriasis limited the progress in its treatment. We review the path taken to enhance our understanding of this complex skin disease as well as the discovery of the varied treatments which initially were serendipitously indentified followed over the decades by ones based on scientific knowledge. The further understanding of this disease has allowed for continued progress and specificity of these modalities as well as the identification of the associated co-morbid conditions. The history of psoriasis, therefore requires an appreciation of how the understanding of this disease has progressed over time in parallel with its evolving treatment options.
Benjamin H Kaffenberger,1 Thomas M Kaffenberger,2 Henry K Wong1 1College of Medicine, Ohio State University, Columbus, OH, USA; 2German Cancer Research Center (DKFZ), Heidelberg, Germany Abstract: The treatment of psoriasis has been revolutionized since the introduction of biologic therapies. Prior to their introduction, it was unclear if psoriasis was primarily a keratinocyte signaling dysfunction or an autoimmune T-cell mediated pathway. Nonspecific T-cell targeting treatments had been used with some success, but they were limited by a narrow therapeutic index. The nonspecific nature of these agents was fraught with side effects, and the efficacy of these treatments pales in comparison to current treatments. The initial biologic molecules, alefacept and efalizumab, were not specific for any T-cell driven pathway, and neither are currently available in the USA. The successors to these early therapies have shown high efficacy and low side effects in psoriasis and other autoimmune diseases through the specific targeting of tumor necrosis factor-alpha (TNF-α). Since the initial use of antitumor necrosis factor agents, a renaissance in our understanding of psoriasis has been underway, leading to the elucidation of the T-helper 17 (Th17) from the Th1 pathway. With each new treatment, the pathogenesis for psoriasis continues to be more defined, allowing for improved targeted therapies and the ability to achieve new milestones in efficacy. Keywords: psoriasis vulgaris, pathophysiology, immunology, T-cell signaling, biologic therapies, psoriasis treatment
Angiogenesis is the formation of new capillaries from pre-existing vasculature, which plays a critical role in the pathogenesis of several inflammatory autoimmune diseases such as rheumatoid arthritis (RA), spondyloarthropathies, psoriasis, systemic lupus erythematosus, systemic sclerosis, and atherosclerosis. In RA, excessive migration of circulating leukocytes into the inflamed joint necessitates formation of new blood vessels to provide nutrients and oxygen to the hypertrophic joint. The dominance of the pro-angiogenic factors over the endogenous angiostatic mediators triggers angiogenesis. In this review article, we highlight the underlying mechanisms by which cells present in the RA synovial tissue are modulated to secrete pro-angiogenic factors. We focus on the significance of pro-angiogenic factors such as growth factors, hypoxia-inducible factors, cytokines, chemokines, matrix metalloproteinases, and adhesion molecules on RA pathogenesis. As pro-angiogenic factors are primarily produced from RA synovial tissue macrophages and fibroblasts, we emphasize the key role of RA synovial tissue lining layer in maintaining synovitis through neovascularization. Lastly, we summarize the specific approaches utilized to target angiogenesis. We conclude that the formation of new blood vessels plays an indispensable role in RA progression. However, since the function of several pro-angiogenic mediators is cross regulated, discovering novel approaches to target multiple cascades or selecting an upstream cascade that impairs the activity of a number of pro-angiogenic factors may provide a promising strategy for RA therapy.
Progressive multifocal leukoencephalopathy (PML) is a rare, complex opportunistic infection of the central nervous system caused by the JC virus. This past decade, PML was increasingly recognized to be associated with the use of immunosuppressive and biologic agents. The risk for PML differs among these agents and remains difficult to quantify because of the complex pathogenesis of PML and the presence of confounding factors. This paper explores and updates the association of PML with different biologic and immunosuppressive agents and proposes an expanded classification system for the risk of PML. We identify three classes of drug that vary by PML risk, latency to infection, and underlying illness. We also review some of the most common agents with known associations to PML and explore risk mitigation strategies that aim to inform the decision-making process for clinicians and patients in the face of the changing incidence of PML and the growing landscape of immunologic agents.
We conducted a systematic review and metaanalysis of randomized placebo-controlled trials in moderate-to-severe psoriasis treated with biological agents, with a follow-up of 10-14 weeks. Overall, 41 studies, with mean Jadad score of 4.4, and 15,586 patients were included. For the efficacy outcomes PASI 50, 75 and 90 our findings are not conclusive to point what biological agent has the greatest response in short term follow-up. There were no statistical differences between placebo and biologics for the occurrence of infections and serious adverse events. Ustekinumab 45mg showed lower withdrawal due to adverse events compared with the placebo. Based on data available up to now, it is not possible to determine which biological agent is the best for PASI 50, 75 or 90 after 10-14 weeks of treatment. At the same follow-up, overall safety seems to be the same for all biological agents and Ustekinumab 45mg the most well tolerated drug. To better understand efficacy and safety, indirect meta-analysis comparing drug-to-drug is required since randomized placebo-controlled trials may not be feasible.
To perform a systematic review and meta-analysis of randomized controlled trials (RCT’s) reporting efficacy of systematic treatments approved for moderate-to-severe psoriasis by means of the Psoriasis Area And severity Index (PASI). I identified relevant articles by systematic electronic searches (Cochrane Library, Medline,). Efficacy was defined as proportion of participants with > 75% decrease in PASI (PASI-75) at primary efficacy measurement (week8-16). PASI-75 response rates of double-blind placebo-controlled trials were summarized as risk differences (RDs) and pooled using random effect models. Tolerability was assessed from rates of withdrawals and adverse events. Twenty-one RCT’s totaling 7877 patients were analyzed qualitatively. Sixteen double-blind placebo-controlled trials were eligible for meta-analysis. Infliximab was significantly superior to all other interventions (RD 77%, 95% confidence interval (CI) 72-81%). Adalimumab (RD 64%, 95% CI 61-68%) was superior to efalizumab (RD 24%, 95% CI 19-30%). Etanercept 50 mg twice weekly (RD 44%, 95% CI 40-48%) and etanercept 25 mg twice weekly (RD 30%, 95% CI 25-35%). Rates of withdrawals due to adverse events were highest for methotrexate and fumaric acid esters.
There are considerable differences in efficacy between systemic biologic therapies which are approved for the treatment of moderate-to-severe psoriasis. Infliximab is most efficacious, followed by adalimumab. Patients receiving infliximab have an excess chance of 77% over placebo to achieve PASI-75 response. Published evidence questions regulatory guidelines that recommend biologics as second-line therapy for moderate-to-severe plaque psoriasis.
Psoriasis vulgaris is an inflammatory skin disease that is generally chronic and that affects between 1 % and 2 % of the population in industrialized Western countries. It is associated with a marked decline in quality of life. A wide range of treatments are currently available, although surveys conducted before the advent of biologic agents reflected a strong degree of dissatisfaction with the treatments then available. Extensive scientific evidence has been gathered on the safety of biologic agents, and this has led to a review of the role of systemic treatment in general and has allowed new therapeutic goals and strategies to be contemplated in patients with moderate-to-severe psoriasis. In this new situation, there is a need for Spanish guidelines on the treatment of moderate-to-severe psoriasis with biologic agents, drafted by consensus among specialists and ratified by the Spanish Psoriasis Group of the Spanish Academy of Dermatology and Venereology (AEDV). These guidelines should be evidence-based with regard to the pharmacologic characteristics, mechanism of action, administration route and regimen, efficacy, contraindications, adverse effects, and cost estimates of biologic agents approved for the treatment of moderate-tosevere psoriasis in Spain.
Systemic therapy for psoriasis has undergone a considerable metamorphosis. Traditional agents, such as methotrexate, cyclosporin and systemic retinoids (predominantly acitretin), have dominated systemic therapy over the past 35 years, with second-tier systemic agents, such as fumaric acid, also known to be beneficial. With the primary role of activated T cells in the immunopathogenesis of psoriasis, targeted biological therapy has finally come of age. This article will review the traditional agents, as well as two main groups of biological drugs: T-cell agents (alefacept and efalizumab) and tumor necrosis factor antagonists (adalimumab, etanercept, and infliximab). Lessons learned from the use of this latter group of drugs in the disciplines of rheumatology (rheumatoid arthritis) and gastroenterology (Crohn's disease) are reviewed, together with a summary of each individual drug. Potential new biological drugs over the ensuing 5 years are likely to further increase the scope of systemic therapy for psoriasis, the most exciting of which is an anti-interleukin-12 molecule, which has recently completed Phase II clinical studies. Dermatologists and patients alike are indeed fortunate to have this therapeutic arsenal available to them for a systemic disease that is frequently neglected, but with major quality of life implications on a par with other major chronic diseases.
Psoriasis is a common, chronic disease with a significant impact on patients and is frequently under-treated. Approval of infliximab for use in plaque psoriasis by the US FDA in late 2006 represents the second tumor necrosis factor-alpha (TNF-α) antagonist approved for patients with moderate-to-severe psoriasis. Infliximab is a monoclonal antibody that binds to and inactivates the TNF- alpha receptor, an important mediator of inflammation in psoriasis. Infliximab, when infused intravenously at regular intervals, has impressive efficacy as a potent systemic treatment for psoriasis. Although long-term safety questions persist, infliximab is well tolerated and appears to be safe with appropriate monitoring. While no single biologic may be best for all patients, infliximab has some distinct advantages over other biologic therapies and is an important treatment option for patients with psoriasis.
Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European populations. Over the last few years, one of the major focuses in psoriasis research has been the development of biological therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. The goal of this article is to update the progress of the tumor necrosis factor inhibitors that are available, or under investigation, for clinical use in psoriasis: infliximab, etanercept and adalimumab, as well as the T-cell-targeted therapies efalizumab and alefacept.
Psoriasis is a debilitating skin disorder that affects 2% of the Caucasian population. In those with moderate-to-severe disease, treatment is challenging, with many cases ultimately proving refractory to traditional systemic therapies, such as methotrexate. For this group of patients, biologic therapies have emerged as novel, targeted approaches for management. One of these, the anti-TNF-α inhibitor adalimumab, is the focus of this article, with emphasis on its pharmacology, clinical efficacy and safety profile.
In reaction to the marketing suspension recommended by the European Medicines Agency, Genentech announced the voluntary withdrawal of efalizumab. Since June 8, 2009, efalizumab has been unavailable. Despite the fact that the use of efalizumab is now ceased, results of studies with efalizumab will remain relevant, especially about its use in an off-label setting for indications other then chronic plaque psoriasis. New biologics as well as chemicals are being developed targeting similar T-cell-mediated pathways. Indications for these new compounds other than chronic plaque psoriasis could be selected based on this systematic review. With this article we aimed to summarize the evidence of effectiveness and/or the efficacy and safety of efalizumab in off-label dermatological use, and to illustrate the time scale in which dermatological medicines are offered off-label to dermatological patients. We found some evidence supporting the effectiveness of efalizumab in palmoplantar pustulosis, atopic dermatitis, lichen planus and cutaneous lupus erythematosus. In total, 12 serious adverse events occurred, one due to an infection. Efalizumab was given off-label within half a year after registration of the drug for plaque psoriasis.
Progressive multifocal leukoencephalopathy (PML) is a severe, often fatal, opportunistic viral infection of the central nervous system that is mainly seen in the context of AIDS and certain monoclonal immune-suppressive therapies. The causative agent, a polyoma virus, named JC virus infects only humans and there is no animal model for PML. This update focuses on information gathered in recent years on the pathogenesis of the disorder, on several clinical aspects associated with diagnosis and therapy, and on the immune reconstitution inflammatory syndrome (IRIS), a complication associated with removal of immunosuppressive therapy in PML.
Introduction
Psoriasis is a debilitating, chronic inflammatory systemic disease affecting around 2% of the South American population. Biological therapies offer the possibility of long-term therapy with improved safety and efficacy.
Methods
We conducted a multicentre, open-label, single-arm, Phase IIIb/IV study of adult patients (18–75 years) with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy. Patients received efalizumab subcutaneously (1.0 mg/kg/wk). The primary endpoint was the proportion of patients achieving a Physician Global Assessment (PGA) rating of “excellent” or “cleared” at Week 24. Safety outcomes were adverse events (AEs), serious AEs (SAEs) and abnormalities on laboratory tests.
Results
Of 189 patients included in the intent-to-treat and safety populations, 104 (55.0%) were of Hispanic or Latino ethnicity. At Week 24, 92/189 (48.7%) patients achieved or maintained a PGA rating of “excellent” or “cleared”. AEs were reported by 161/189 (85.2%) patients, SAEs by 21/189 (11.1%). One patient died during the study (meningoencephalitis). Laboratory findings were consistent with previous experience.
Conclusions
Efalizumab demonstrated sustained control of psoriasis up to 24 weeks in patients from Latin America, confirming results seen in Phase III studies conducted in North America and Europe.
Biologics are approved for the therapy of psoriasis and psoriatic arthritis as well as a number of nondermatologic indications.
Biologics include cell adhesion molecule antagonists (alefacept and efalizumab) and cytokine antagonists (etanercept, infliximab, and adalimumab).
Biologics appear relatively safe, but clinical and laboratory monitoring of safety is recommended.
Cytokine (i.e., tumor necrosis factor) antagonists have other potential uses in dermatology, including pyoderma gangrenosum, hidrandenitis suppurativa, and sarcoidosis.
Future biologics will include interleukin-12/interleukin- 23-targeted therapies.
The treatment of psoriasis has long been a challenge to the dermatologist on several levels. Psoriasis does not respond in
any predictable fashion to topical or systemic agents, and to date there are no clinical or laboratory measures to predict
response to therapy in an individual. In clinical practice, emphasis on impact of the disease and its treatment on a patient’s
quality of life and health should guide treatment choices. Severity of disease, including location and body surface area,
response to previous therapies, medical history, concomitant medications, treatment goals, convenience of administration,
and financial limitations, must all be considered carefully when choosing initial therapy. Because in any given patient severity
and impact of disease will fluctuate over time and with different therapies, frequent reassessment of symptoms, treatment
satisfaction, and short- and long-term side effects of therapy is a necessary approach.
INTRODUCTION:
Plaque-type psoriasis affecting the nails, scalp, hands or feet can often be difficult to treat; for example, topical treatments and phototherapy may not penetrate the nail plate or scalp. The objective of this large, international, multicentre study was to investigate the efficacy of efalizumab in a Latin American population of adult patients with moderate-to-severe chronic plaque psoriasis who were candidates for systemic therapy or phototherapy.
METHODS:
Eligible patients were enrolled in a 24-week, open-label, single-arm, Phase IIIb/IV study of continuous treatment with subcutaneous efalizumab, 1.0 mg/kg/wk. Involvement of the nails, scalp, or hands or feet was assessed using the Nail Psoriasis Severity Index (NAPSI), the Psoriasis Scalp Severity Index (PSSI), or the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI), respectively. Missing data were handled using a last observation carried forward or nonresponder imputation approach.
RESULTS:
Of the 189 patients who received treatment, 112 patients had nail involvement, 172 had scalp involvement, and 19 had palmoplantar disease at baseline. At Week 24, >/=50% improvement on the NAPSI, PSSI and PPPASI was observed in 31%, 71% and 68% of patients, respectively, whereas >/=75% improvement on these scores was observed in 17%, 52% and 63%, respectively. Descriptive statistics showed lower NAPSI-75 and higher PSSI-75 and -50 response rates among patients with higher baseline scores.
CONCLUSIONS:
This open-label, uncontrolled study provides supportive evidence of the potential of efalizumab as a treatment for nail, scalp and palmoplantar psoriasis.
Introduction:
The conventional treatment of uveitis includes corticosteroids and immunosuppressive agents, which are highly efficacious, but can be associated with serious systemic side effects. Over the last two decades, advances in the understanding of the pathogenesis of inflammatory diseases, as well as improved biotechnology, have enabled selective targeting of the chemical mediators of diseases. Recently, a new class of drugs called biologics, that target the various mediators of the inflammation cascade, may potentially provide more effective and less toxic treatment.
Areas covered:
This article is a review and summary of the peer-reviewed evidence for biologic agents in the treatment of various forms of ocular inflammation and it focuses on the potential use of other biologic agents that have been tested in experimental autoimmune uveitis. Pubmed was used as our main tool for our literature search. Some additional references were taken from books written on the subject.
Expert opinion:
There are a wide variety of new and emerging biological agents currently being used in the treatment of uveitis which has expanded the therapeutic horizons far beyond previous limitations.
Background:
The patient-reported Dermatology Life Quality Index (DLQI) measures the impact of dermatologic diseases on patients' lives.
Objectives:
To evaluate the content validity of the DLQI in patients with moderate to severe plaque psoriasis.
Methods:
In a two-part interview, participants were first asked open-ended questions about the impact of psoriasis-related complaints and symptoms on their lives and activities. The DLQI was then administered and cognitive debriefing interviews assessed participants' understanding of the instructions, items, and response scales, and relevance of the specific items to their experience with psoriasis.
Results:
Twenty-one patients were interviewed at two US sites. Mean age was 48.8 years, 67% were white, and 43% reported Hispanic/Latino ethnicity. The majority reported living with a partner or spouse (81%) and working full time or part time (57%). Patients' spontaneous responses to open-ended questions were consistent with DLQI concepts and generally did not provide additional concepts. Most participants reported that the instructions, item content, and response scales were clear and easy to understand and relevant.
Conclusions:
The content of the DLQI included all important and relevant concepts from the perspective of patients with moderate to severe plaque psoriasis. This study provides further support for the content validity of the DLQI in this population.
Targeted biologic therapies have revolutionised treatment of immune-mediated inflammatory diseases (IMIDs) due to their efficacy, speed of onset and tolerability. The discovery that clinically unrelated conditions, such as rheumatoid arthritis and Crohn's disease, share similar immune dysregulation has led to a shift in the management of IMIDs from one of organ-based symptom relief to mechanism-based treatment. The fact that anticytokine therapy has been effective in treating multiple orphan inflammatory conditions confirms the IMID paradigm. In this review we examine the biologic agents currently licensed for use in the US and Europe: infliximab, etanercept, adalimumab, rituximab, abatacept, anakinra, alefacept and efalizumab. We also discuss the rationale behind the management of IMIDs using rheumatoid arthritis, Crohn's disease, psoriasis and psoriatic arthritis as examples. For the medical profession, IMID represents a breakthrough in the way pathology is classified. In this burgeoning era of biologic therapy the prospect of complete disease remission is conceivable.
Psoriasis is a chronic inflammatory systemic disease for which there exist topical, ultraviolet, systemic, and biologic treatments. Biologic agents selectively interfere with the immune mechanisms responsible for psoriasis. Etanercept, infliximab, and adalimumab target tumor necrosis factor-alpha and have demonstrated efficacy in the treatment of psoriasis and psoriatic arthritis. Alefacept and efalizumab target T lymphocytes, are effective in the treatment of psoriasis, but are not approved for psoriatic arthritis. Finally, ustekinumab and ABT-874 target interleukin-12 and interleukin-23, and they have demonstrated efficacy in the treatment of psoriasis. The objective of this review is to present efficacy and safety data from randomized controlled trials of the biologic agents in the treatment of psoriasis.
Introduction:
Conventional systemic therapies for psoriasis are associated with serious toxicities that can limit long-term use. In recent years, biological therapies have offered the possibility of long-term therapy with improved safety and efficacy for the treatment of psoriasis. Biological therapies can be classified into three categories: the T-cell modulating agents (alefacept and efalizumab), the inhibitors of TNF-α (adalimumab, etanercept, infliximab) and the inhibitors of IL-12 and -23 (ustekinumab). Efalizumab is a humanized recombinant monoclonal IgG1 antibody. It targets multiple stages in the immunopathogenesis of psoriasis: initial T-cell activation, migration of T-cells into dermal and epidermal tissues, and T-cell reactivation. On 19 February 2009, the Committee for Medicinal Products for Human Use (CHMP) recommended the suspension of the marketing authorisation for efalizumab.
Areas covered:
Numerous clinical trials have demonstrated the efficacy, safety and health-related quality of life benefits of efalizumab in patients with moderate-to-severe chronic plaque psoriasis. Efalizumab was approved by the FDA in November 2003 and by the European Medicines Evaluation Agency in September 2004 for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis. Recently, three cases of progressive multifocal leukoencephalopathy were described in patients on long-term (> 3 years) efalizumab therapy, leading to its withdrawal from the market.
Expert opinion:
Although initially favorable, the safety profile of efalizumab revealed the appearance of severe adverse events in long-term treated patients. Therefore, post-marketing surveillance is essential for correct evaluation of drug potential.
Efalizumab is a monoclonal antibody targeting CD11a, an adhesion molecule involved in the activation and trafficking of T-lymphocytes. This agent has proven efficacy in the treatment of psoriasis. We performed an open-label study to evaluate the efficacy and safety of efalizumab in Crohn's disease (CD).
Fifteen subjects with moderate to severe CD (Crohn's Disease Activity Index [CDAI] score 220-450) and who were refractory or intolerant to standard therapy, received a weekly 1 mg/kg subcutaneous injection of efalizumab for 8 weeks. The primary endpoint was clinical response (decrease in the CDAI score of at least 70 points) at week 8. Secondary endpoints included change in mean CDAI scores, the proportion of subjects who achieved clinical remission (CDAI score ≤ 150), change in the Inflammatory Bowel Disease Questionnaire (IBDQ) scores, and report of adverse events.
At 8 weeks, ten (67%) subjects had clinical response and six (40%) were in remission. The mean baseline and week 8 CDAI scores were 300 and 167 respectively (P < 0.001). Mean IBDQ scores at baseline and week 8 were 124 and 168 respectively (P < 0.001). One subject with Crohn's colitis had pre- and post-treatment colonoscopy that demonstrated mucosal healing. No serious adverse events occurred.
Efalizumab induced a clinical response in the majority of subjects with moderate to severe CD in this small, open-label pilot study. There were no serious adverse events reported during this short-term trial.
The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so far, pharmacological inhibitors for only three integrins have received marketing approval. This article discusses the structure and function of integrins, their roles in disease and the chequered history of the approved integrin antagonists. Recent advances in the understanding of integrin function, ligand interaction and signalling pathways suggest novel strategies for inhibiting integrin function that could help harness their full potential as therapeutic targets.
We report a case of disseminated human papillomavirus infection that developed in a patient while receiving efalizumab for
the treatment of psoriasis. This infection progressed for several months after efalizumab treatment had been stopped. All
human papillomavirus lesions completely resolved after 10 weeks of therapy with a combination of pegylated interferon and
ribavirin.
Recent epidemiological observations reveal that the prevalence of psoriasis increases more rapidly in young women compared with young men, and that the prevalence of psoriasis may decrease in the elderly. Emerging evidence suggests that some potentially modifiable exposures, such as smoking, stress and obesity, may increase a patient's risk of developing psoriasis. The evolving literature suggests that psoriasis is associated with multiple other diseases, including cancer, cardiovascular disease, diabetes and psychiatric disease, and that psoriasis itself may be an independent risk factor for developing atherosclerosis and myocardial infarction. The treatment of moderate-to-severe psoriasis is undergoing a revolution with the advent of biological therapies that target the immunopathogenesis of psoriasis, such as tumor necrosis factor-alpha and T-cell function. The pharmacokinetics, pharmacodynamics, efficacy and safety profiles vary among biologicals and, therefore, drug and patient factors are important in selecting the optimum therapy. In this article, we focus on recent developments in the epidemiology and systemic treatment of psoriasis.
Efalizumab was approved for moderate to severe psoriasis in 2003 based on studies in approximately 2700 patients, of whom only 218 were exposed to the drug for more than 1 year. In 2009, after more than 46,000 patients were exposed to efalizumab, the drug was withdrawn from the market after 3 confirmed and 1 suspected case of progressive multifocal leukoencephalopathy (PML) were spontaneously reported. As PML is very rare, it is extremely unlikely that the 4 reported cases were due to chance and given that PML occurs primarily in patients who are immunosuppressed, the association is likely causal. The identification of PML as a serious, but statistically rare risk of efalizumab demonstrates the strengths and weaknesses of the current drug approval and pharmacovigilance processes for fully measuring the safety of a drug. Patients and clinicians need to be aware of the relative completeness and limitations of existing safety data of a drug when selecting a treatment.
Objectives
To evaluate the efficacy and safety of efalizumab in continuous or interrupted therapy of adults with moderate-to-severe plaque psoriasis who had failed to respond to or were intolerant of other systemic therapies, including methotrexate, ciclosporin and psoralen plus UVA phototherapy, or for whom such therapies were contraindicated.
Methods
Patients received a conditioning dose of efalizumab 0.7 mg/kg followed by once-weekly open-label efalizumab 1.0 mg/kg for 11 weeks. Responders (Physician Global Assessment [PGA] score of “good” or better at Week 12) could continue efalizumab for a further 8 weeks (continuous-treatment period). Nonresponders transitioned to alternative anti-psoriasis medication or stopped treatment. Responders who discontinued efalizumab could restart treatment if symptoms worsened. PGA response was evaluated at Weeks 12 (primary endpoint) and 20, as were the proportions of patients achieving an improvement from baseline of ≥50%, ≥75% and ≥90% in Psoriasis Area and Severity Index (PASI) (PASI 50, PASI 75 and PASI 90, respectively).
Results
A total of 1,255 patients were included in the intention-to-treat population. At Week 12, 68.0% of patients had a PGA rating of “good” or better. Of 688 patients who entered the continuous-treatment period, 79.5% had a PGA rating of “good” or better at Week 20. At Week 12, median improvement in PASI score was 68.4%. PASI 50/75/90 was achieved by 65.5%/35.9%/13.0% of patients at Week 12, and by 78.2%/52.9%/24.3% of responders at Week 20. Of the 127 responders at Week 12 who discontinued efalizumab, 11% experienced rebound and 56.7% relapsed within 8 weeks after stopping therapy. Efalizumab was well tolerated during the study.
Conclusions
Efalizumab provided effective control of psoriasis in the majority of patients during the initial treatment period. The high response rates were maintained in initial responders when treatment was continued beyond 12 weeks.
T cell-directed therapies have become mainstays in the management of various autoimmune diseases and organ transplantation. The understanding of T cell biology has expanded greatly since the development of most agents currently in use. Here we discuss important recent discoveries pertaining to T helper cell differentiation, lineage commitment, and function. Within this context, we examine existing T cell-directed therapies, including new agents being evaluated in clinical and preclinical studies. We also use recent findings to speculate on novel targets.
This post-approval, open-label trial (n = 1266) assessed the efficacy of efalizumab, administered in accordance with the European label at that time, in patients with concomitant nail, scalp or palmoplantar psoriasis. Patients received subcutaneous efalizumab 1.0 mg/kg weekly for up to 20 weeks. By Week 12, an improvement from baseline of 50% or more was observed in 21.4% (181/844) of patients with nail psoriasis, 62.4% (718/1150) of patients with scalp psoriasis, and 51.4% (127/247) of patients with palmoplantar psoriasis. Quality of life improved throughout the trial, with a 50% median improvement in DLQI score after 12 weeks of treatment. Efalizumab showed promising efficacy in the treatment of nail, scalp and palmoplantar psoriasis, which was reflected in improvements in quality of life.
During the last 30 years, the tremendous progress in our knowledge of the pathogenesis of psoriasis has led to the development of new agents, the so-called biologics, that have revolutionized the management of severe psoriasis. Dermatologists and patients see this emerging therapy as a new perspective in the state of the art in managing moderate to severe psoriasis. After a few years of use in daily practice, we may begin to analyze the power of the currently available biologic agents in the management of severe psoriasis from the perspective of facts.
The strong but complex genetic background suggests that inherent and intrinsic rather than exogenous factors have a key role in immunopathogenesis of psoriasis. It is reasonable to speculate that the dysfunctional activity of psoriatic T cells may partly originate from the abnormal haematopoietic cells.
To test if T cells originated from haematopoietic progenitor cells in psoriasis patients display functional alternations similar to previously reported abnormalities of circulating T cells.
Bone marrow CD34(+) haematopoietic cells were isolated from psoriatic patients with family history and healthy subjects, and differentiated into T cells in vitro in the thymic stromal co-culture system. These cells were further subjected to functional comparisons such as in vitro proliferation, secretion of cytokines such as IL-4, IL-8 and IFN-gamma, and inducing the production of C-myc, Bcl-xL, and Ki67 proteins in human keratinocytes.
While bone marrow-derived CD34(+) cells from both patients and healthy volunteers developed into mature T cells within weeks in the thymic environment in vitro, the differentiated T cells from psoriatic patients showed higher proliferation and stronger capacity to secret TH1 cytokines in response to streptococcal superantigen. The differentiated T cells from psoriatic patients, but not from normal controls, induced overexpression of C-myc and Ki67, but not Bcl-XL, in keratinocytes.
T cells differentiated from CD34(+) cells of psoriatic patients, but not normal controls, are functionally similar to psoriatic circulating T cells, suggesting that the dysfunctional activity of T cells in psoriatic patients can be traced back to the early development of haematopoietic cells.
Psoriasis is a chronic skin disease that can impact heavily on a patient's well-being. Efalizumab, a unique, targeted, biological therapy, has demonstrated efficacy in treating moderate-to-severe, chronic plaque psoriasis with <or=36 months of continuous therapy. The objective of this Extended Access Program (EAP) was to evaluate further the benefit of efalizumab as long-term therapy in a real-world clinical setting.
After an initial conditioning dose of efalizumab (0.7 mg/kg subcutaneously), a weekly dose of efalizumab (1.0 mg/kg) was administered for <or=21 months. Patients with reduced Psoriasis Area and Severity Index (PASI) scores (>or=50%, or a score <or=8) at month 3 entered the long-term maintenance treatment period.
In total, 101 patients (>18 years) with severe plaque psoriasis enrolled on the EAP, of these 93 (92.1%) met all the inclusion criteria. After 3 months of treatment, 84/101 (83.2%) patients had evaluable data and entered the maintenance period. After 3 months, 57/84 (67.9%) patients had achieved PASI-50. Using an intent-to-treat analysis, after 21 months of treatment, PASI-75 and PASI-50 were achieved by 43/101 (42.6%) and 69/101 (68.3%) of patients, respectively. Efalizumab was generally well tolerated during the 21 months of continuous therapy.
Efalizumab, 1.0 mg/kg/week, is effective and well tolerated in a 'real world' clinical setting, providing enduring reduction of psoriasis symptoms for up to 21 months.
Diss. Naturwiss. Basel (kein Austausch). Literaturverz.
Biologic therapies are an efficacious new method of controlling a number of chronic conditions. Data regarding these medications continues to emerge, giving clinicians a greater understanding of their side effects profiles. The biologic agents used in dermatology, particularly the tumor necrosis factor-alpha inhibitors, have a number of varied dermatologic side effects. In this two-part article, we perform a review of literature regarding the cutaneous side effects of infliximab, etanercept, adalimumab, rituximab, efalizumab, and alefacept. In Part 1, we will discuss cutaneous infections, malignancy, rebound phenomenon, eczema, atopic dermatitis, lichenoid reactions, granulomatous disease, pruritus, acne, and progressive multifocal leukoencephalopathy.
Of the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.
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