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ImmunoTargets and Therapy 2013The treatment of psoriasis has been revolutionized since the introduction of biologic therapies. Prior to their introduction, it was unclear if psoriasis was primarily a... (Review)
Review
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.
PubMed: 27471688
DOI: 10.2147/ITT.S32038 -
Arthritis Research & Therapy Sep 2012Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that... (Clinical Trial)
Clinical Trial Comparative Study
INTRODUCTION
Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T-cell activation) has been shown to result in improvement in psoriasis but has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key proinflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown.
METHODS
Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open-label study. Skin biopsies were taken before and after 1 and 6 weeks, whereas synovial biopsies were obtained before and 4 and 12 weeks after treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n = 10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated with digital image analysis. Double staining was performed with IL-20 and CD68 (macrophages), and conversely with CD55 (fibroblast-like synoviocytes, FLSs) to determine the phenotype of IL-20-positive cells in PsA synovium. IL-20 expression in skin sections (n = 6) was analyzed semiquantitatively.
RESULTS
IL-20 was abundantly expressed in both PsA and RA synovial tissues. In inflamed PsA synovium, CD68+ macrophages and CD55+ FLSs coexpressed IL-20, and its expression correlated with the numbers of FLSs. IL-20 expression in lesional skin of PsA patients decreased significantly (P = 0.04) 6 weeks after treatment and correlated positively with the Psoriasis Area and Severity Index (PASI). IL-20 expression in PsA synovium was not affected by alefacept.
CONCLUSIONS
Conceivably, the relatively limited effectiveness of alefacept in PsA patients (compared with anti-tumor necrosis factor (TNF) therapy) might be explained in part by persistent FLS-derived IL-20 expression.
Topics: Adult; Alefacept; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Arthritis, Psoriatic; Arthritis, Rheumatoid; Biopsy; CD55 Antigens; Dermatologic Agents; Dose-Response Relationship, Drug; Female; Humans; Interleukins; Male; Middle Aged; Prospective Studies; Recombinant Fusion Proteins; Skin; Synovial Membrane; Time Factors; Treatment Outcome
PubMed: 23006144
DOI: 10.1186/ar4038 -
The Journal of Allergy and Clinical... Sep 2012Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration... (Review)
Review
Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders.
Topics: Alefacept; Alemtuzumab; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal, Humanized; Cell Movement; Clinical Trials as Topic; Eosinophils; Humans; Hypereosinophilic Syndrome; Interleukin-5; Omalizumab; Phosphorothioate Oligonucleotides; Recombinant Fusion Proteins
PubMed: 22935585
DOI: 10.1016/j.jaci.2012.07.027 -
American Journal of Transplantation :... Sep 2012Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in...
Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics.
Topics: Animals; Graft Rejection; Graft Survival; Immunohistochemistry; Immunologic Memory; Immunosuppressive Agents; Isoantibodies; Lymphocyte Depletion; Macaca mulatta; Male
PubMed: 22776408
DOI: 10.1111/j.1600-6143.2012.04074.x -
PloS One 2012While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and... (Review)
Review
OBJECTIVES
While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment) with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment.
DATA SOURCES AND STUDY SELECTION
We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept.
DATA SYNTHESIS
A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited.
CONCLUSION
Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent results in superior efficacy over interrupted therapy. The decision to use off-label dosing needs to account for both benefits and risks and be individualized to patients' disease severity, quality of life, and existence of comorbidities.
Topics: Drug Approval; Drug Dosage Calculations; Humans; Off-Label Use; Psoriasis; Safety; Withholding Treatment
PubMed: 22509259
DOI: 10.1371/journal.pone.0033486 -
American Journal of Transplantation :... Jul 2012Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the...
Immunosuppressive therapies that block the CD40/CD154 costimulatory pathway have proven to be uniquely effective in preclinical xenotransplant models. Given the challenges facing clinical translation of CD40/CD154 pathway blockade, we examined the efficacy and tolerability of CD40/CD154 pathway-sparing immunomodulatory strategies in a pig-to-nonhuman primate islet xenotransplant model. Rhesus macaques were rendered diabetic with streptozocin and given an intraportal infusion of ≈ 50 000 islet equivalents/kg wild-type neonatal porcine islets. Base immunosuppression for all recipients included maintenance therapy with belatacept and mycophenolate mofetil plus induction with basiliximab and LFA-1 blockade. Cohort 1 recipients (n = 3) were treated with the base regimen alone; cohort 2 recipients (n = 5) were additionally treated with tacrolimus induction and cohort 3 recipients (n = 5) were treated with alefacept in place of basiliximab, and more intense LFA-1 blockade. Three of five recipients in both cohorts 2 and 3 achieved sustained insulin-independent normoglycemia (median rejection-free survivals 60 and 111 days, respectively), compared to zero of three recipients in cohort 1. These data show that CD40/CD154 pathway-sparing regimens can promote xenoislet survival. Further optimization of these strategies is warranted to aid the clinical translation of islet xenotransplantation.
Topics: Animals; CD40 Antigens; CD40 Ligand; Cohort Studies; Diabetes Mellitus, Experimental; Graft Survival; Heterografts; Immunologic Memory; Immunosuppressive Agents; Islets of Langerhans Transplantation; Macaca mulatta; Swine; T-Lymphocytes
PubMed: 22458586
DOI: 10.1111/j.1600-6143.2012.04031.x -
Reumatologia Clinica Mar 2012Registries estimate that one third of patients with psoriatic arthritis (PsA) are "resistant" to of TNF-alpha blockers. Therefore, the search for new approaches to... (Review)
Review
Registries estimate that one third of patients with psoriatic arthritis (PsA) are "resistant" to of TNF-alpha blockers. Therefore, the search for new approaches to treatment of this disease may be justified. Currently the treatment options that have proven effective are associated with inhibition of the T cell costimulatory pathway (abatacept and alefacept) and blocking the P40 fraction of IL-12 and IL-23 (ustekinumab). A novel pathway inhibition, which deserves special attention is offered by apremilast. This molecule inhibits phosphodiesterase IV, responsible for hydrolyzing cyclic adenosine monophosphate to adenosine monophosphate, which causes an increase in cAMP. This metabolite is associated with decreased TNF-alpha. It has a modest efficacy (ACR 20 response of 43%), and subsequent studies have shown an improvement in visual analog scale and the SF36 compared to placebo. Currently there are five clinical trials in phase III to assess its effectiveness in parameters of inflammation and radiographic progression. The spectrum of possibilities before treatment failure with anti-TNF alpha, is augmented by the appearance of several reports that show efficacy with the individual use of CD20 inhibitors and IL-1. In patients with rheumatoid arthritis (RA) the effectiveness of molecules that inhibit signal transduction of cytokines (Anti-JAK) has been proven, so it is possible that in the future they may be used in patients with PsA.
Topics: Aminopyridines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antirheumatic Agents; Arthritis, Psoriatic; Bone Remodeling; Clinical Trials, Phase III as Topic; Cyclic AMP; Cytokines; Denosumab; Disease Progression; Drug Resistance; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Janus Kinases; Lymphocyte Activation; Lymphocyte Depletion; Molecular Targeted Therapy; Morpholines; Oxazines; Phosphodiesterase 4 Inhibitors; Pyridines; Pyrimidines; T-Lymphocyte Subsets; Thalidomide; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 22421457
DOI: 10.1016/j.reuma.2012.01.003 -
Dermatology Online Journal Feb 2012Practice varies with respect to biologic therapy counseling and monitoring of biologic therapy. Because of the complexity, many physicians shy away from prescribing... (Review)
Review
BACKGROUND
Practice varies with respect to biologic therapy counseling and monitoring of biologic therapy. Because of the complexity, many physicians shy away from prescribing biologic therapy.
OBJECTIVE
To create checklists and discuss considerations behind various counseling and monitoring issues.
METHODS
The full prescribing information of infliximab, etanercept, adalimumab, golimumab, certolizumab, alefacept, ustekinumab, rituximab, and IVIg were reviewed in addition to National Psoriasis Foundation guidelines to create the checklists.
RESULTS
Considerations of counseling for biologics includes explaining benefits, relative risks of not treating or alternative therapies, consequence of risk, preventability of risk, and likelihood of risk. Considerations regarding vaccination, viral hepatitis screening, tuberculosis screening, skin cancer screening, pregnancy, and anti-nuclear antibody screening are discussed.
LIMITATIONS
Consensus is unavailable as to the extent of counseling or monitoring. This manuscript provides one perspective.
CONCLUSIONS
This article reviews monitoring and patient counseling considerations for the use of biologics in dermatology. Tables for each drug are provided with checklists for counseling and monitoring.
Topics: Biological Therapy; Directive Counseling; Female; Humans; Pregnancy; Risk; Skin Diseases; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha
PubMed: 22398223
DOI: No ID Found -
British Journal of Pharmacology Jun 2012Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this... (Review)
Review
Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions'; and the US Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found.
Topics: Animals; Antibodies, Monoclonal; Drug Evaluation, Preclinical; Humans; Maximum Tolerated Dose; No-Observed-Adverse-Effect Level; Pharmacology, Clinical; Predictive Value of Tests; Receptors, Cell Surface; Recombinant Fusion Proteins; Solubility; Species Specificity
PubMed: 22168282
DOI: 10.1111/j.1476-5381.2011.01811.x