Etanercept: an updated review of its use in rheumatoid arthritis,psoriatic arthritis and juvenile rheumatoid arthritis

Etanercept is a subcutaneously administered biological response modifier that binds and inactivates tumour necrosis factor-alpha, a proinflammatory cytokine. In patients with early active rheumatoid arthritis, etanercept 25mg twice weekly was associated with a more rapid improvement in disease activity and a significantly greater cumulative response than methotrexate over 12 months of treatment in a randomised, double-blind trial. In addition, etanercept recipients showed a slower rate of radiographic progression and a more rapid improvement in quality of life than methotrexate recipients. The efficacy of etanercept was maintained at 3 years' follow-up. Etanercept was also significantly better than placebo at reducing disease activity in patients who had an inadequate response to previous treatment with disease-modifying antirheumatic drugs (DMARDs) in several well controlled trials. At study end (after 3 or 6 months' treatment), the percentage of patients achieving an American College of Rheumatology 20% (ACR20) response with etanercept (25mg or 16 mg/m(2) twice weekly) was 59 to 75% as monotherapy and 71% in combination with methotrexate; corresponding placebo response rates were 11 to 14% and 27%, respectively. Response has been maintained in patients who continued treatment for up to 5 years. In patients with psoriatic arthritis, etanercept 25mg twice weekly significantly reduced disease activity and improved skin lesions in two double-blind, placebo-controlled, 12- to 24-week trials. In the 24-week study, ACR20 response rates (50 vs 13%), psoriatic arthritis response rates (70 vs 23%) and the median improvement in skin lesions (33 vs 0%) were significantly greater in etanercept than in placebo recipients. In patients with polyarticular-course juvenile rheumatoid arthritis, etanercept resulted in improvements in all measures of disease activity and was significantly more effective than placebo at reducing disease flare. Eighty percent of patients receiving etanercept achieved a >or=30% reduction in disease activity over 7 months of treatment, and this was maintained for up to 2 years in a trial extension. Etanercept was generally well tolerated in children and adults in clinical trials; the most commonly occurring adverse effects included injection site reactions, infection, headache, rhinitis and dizziness. In conclusion, etanercept has emerged as an important new treatment option in inflammatory arthritis. Etanercept provides rapid and sustained improvements in disease activity in patients with early and DMARD-refractory rheumatoid arthritis and has been shown to inhibit radiographic progression in those with early disease. Well controlled studies have also demonstrated the efficacy of etanercept in patients with psoriatic arthritis or polyarticular-course juvenile rheumatoid arthritis.     

Drug treatment of juvenile arthritis: accepted therapeutic options

Juvenile arthritis (JA) is classified into 3 subtypes based primarily on clinical characteristics (sign and symptoms) at onset. For all patients with JA, drug therapy begins with nonsteroidal antiinflammatory drugs (NSAIDs) from which there are a number of pediatric approved compounds to choose. If disease activity persists after an adequate NSAID trial, a second-line agent, typically methotrexate, is added. In patients with a small number of resistant joints, in the absence of other illness manifestations, intraarticular corticosteroids (triamcinolone hexacetonide) can be used to induce remission. Some children with severe JA, particularly systemic onset disease, will require the addition of systemic corticosteroids for symptom control. Further treatment has been less well evaluated but includes intravenous immunoglobulin, drug combination cytotoxic therapy and biologic agents. The latter will be increasingly studied in the pediatric population in the future, but are currently reserved for severely unresponsive disease. Management of JA extends beyond drugs, to incorporate occupational and physical therapy, appropriate mental health care and a family centered strategy that seeks to achieve the highest attainment and quality of life for these patients and their families.     

Current and emerging biologic and small molecule systemic treatment options for psoriasis and psoriatic arthritis

Psoriasis and psoriatic arthritis are chronic inflammatory diseases affecting the skin and joints, respectively. Psoriasis and psoriatic arthritis are associated with a high comorbidity burden as well as negative impact on quality of life. Impact on health-related quality of life is optimized when both skin and joint manifestations are effectively treated. The identification of key cytokines involved in disease pathogenesis has led to the development of several therapeutic options for psoriatic disease. When selecting a therapy, it is important to consider disease severity, psoriasis disease subtypes or domains of psoriatic arthritis, comorbidities, patient preference for treatment, among other factors. This review summarizes current biologic and small molecule treatment options as well as emerging therapies for moderate-to-severe adult plaque psoriasis and psoriatic arthritis.     

Drug-induced gynecomastia: an evidence-based review

Introduction: Drugs are estimated to cause about 10 - 25% of all cases of gynecomastia. Over the course of several decades, multiple medications have been implicated in the development of gynecomastia mostly in the form of case reports and case series. However, these reports suffer from a multitude of deficiencies, including poor quality of evidence. Areas covered: Studies were selected for this review by performing an extensive electronic and hand-search using BIOSIS, EMBASE and Medline, from 1940 to present, for all reported drug associations of gynecomastia and their possible pathophysiology. Quality of evidence was assessed on a three-point scale: good, fair and poor, and each of the drugs reported to cause gynecomastia was assigned a level of strength. The pathophysiology of gynecomastia is also discussed in detail for each of the drugs found to have a good or fair evidence of association with gynecomastia. Expert opinion: Most of the reported drug-gynecomastia associations were based on poor quality evidence. The drugs definitely associated with the onset of gynecomastia are spironolactone, cimetidine, ketoconazole, hGH, estrogens, hCG, anti-androgens, GnRH analogs and 5-α reductase inhibitors. Medications probably associated with gynecomastia include risperidone, verapamil, nifedipine, omeprazole, alkylating agents, HIV medications (efavirenz), anabolic steroids, alcohol and opioids.     

Lipids and diabetes mellitus: a review of therapeutic options

Diabetes mellitus ia very common disease with a high cardiovascular morbidity and mortality. This articles reviews the types of lipid disorders that can accompany diabetes mellitus and the evidence that treatment of dyslipidaemia improves primary and secondary endpoints, i.e. lipid levels, cardiovascular events, and mortality. Specific lipid-lowering strategies are discussed, including diet and exercise, treatment of hyperglycaemia, and the use of lipid-lowering therapy such as statins, fibric acid derivatives, bile acid sequestrants, nicotinic acid and its derivatives, fish oil and hormone replacement therapy. An approach to the patient with diabetes mellitus and dyslipidaemia is provided.     

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.     

Tumor necrosis factor inhibitors in the management of juvenile idiopathic arthritis: an evidence-based review

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disorder of unknown origin that is often treated with a variety of disease-modifying agents. Tumor necrosis factor (TNF) inhibitors are a group of genetically engineered biologic agents that target the proinflammatory cytokine TNF. This review focuses on the use of TNF inhibitors in JIA. Etanercept was the first TNF inhibitor approved for use in children with moderate to severe polyarticular-course JIA following encouraging results from a randomized, double-blind, placebo-controlled, multicenter trial in children. Open-label extension studies of the original trial involving 8 years of follow-up demonstrated the long-term safety and efficacy of etanercept in children. Other studies from established registries also corroborate the safety of etanercept in JIA. The second TNF inhibitor to be approved for use in JIA is adalimumab following recent favorable results from another randomized, placebo-controlled, multicenter study in polyarticular-course JIA. While infliximab is not approved by the US FDA for use in JIA, it is frequently used in clinical practice for this indication. However, because the chimeric structure of infliximab incorporates murine components, it has the potential for allergic and infusion reactions. Patient responses to individual TNF inhibitors may vary depending on concomitant medications such as methotrexate, and also on the category of JIA.     

Emerging drugs for psoriatic arthritis

Importance of the field: The socioeconomic burden of psoriatic arthritis (PsA) is considerable and not different from that of rheumatoid arthritis. Current treatment options do not always allow reaching the therapeutic objectives consisting of the remission of symptoms and prevention of the appearance of damage in the early stage of PsA or the blocking of PsA progression in the established cases.

Areas covered in this review: After reviewing the current treatment choices, we examine the new drugs in clinical Phase II and III trials for PsA up to January 2010. Information was mainly obtained from the network of international clinical trial registries.

What the reader will gain: The current management of PsA includes NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs) and anti-TNF-α blocking agents. These last drugs are more effective than traditional DMARDs on symptoms/signs of inflammation, quality of life and function and can inhibit the progression of the structural joint damage. Recent advancement in the knowledge of the immunopathogenesis of PsA has permitted the development of novel drugs including new TNF-α blockers, IL-1, -6, -12, -23 and -17 inhibitors, co-stimulator modulation inhibitors, B-cell depleting agents, small molecules and receptor activator of NF-κB/receptor activator of NF-κB ligand inhibitors.

Take home message: The currently available anti-TNF-α blocking agents have revolutionized the management of PsA. However, there is a need for more effective and safer drugs.     

Inhaled aztreonam lysine: an evidence-based review

Introduction: Chronic airway infection in cystic fibrosis (CF) is linked with progressive loss of pulmonary function and is the primary cause of mortality. Treatment regimens have generally focused on the use of chronic antibiotic therapy to target Pseudomonas aeruginosa (PA), a major pathogen associated with a decline in FEV₁%. Specifically, inhaled antibiotic therapy provides high antibiotic sputum concentrations and decreases bacterial burden.

Areas covered: This article describes the pharmacology, pharmacodynamics/pharmacokinetics, clinical efficacy, microbiology and safety of aztreonam lysine (AZLI, Cayston), an inhaled antibiotic indicated for use in CF patients with PA. Articles were identified using MEDLINE (1966 – June 13, 2013) and EMBASE (1947 – June 13, 2013). Abstracts from the annual meeting (2011 – 2012) of the North American Cystic Fibrosis Conference were searched to identify additional publications.

Expert opinion: AZLI is an additional product that can be used in the management of CF and will likely play a major role in the suppression of PA. Clinical trials have demonstrated improvements in pulmonary function and patient reported symptoms. AZLI may therefore be used as an alternative to traditional inhaled antibiotics in patients with moderate-to-severe CF and PA colonization. Further investigation is warranted into use of AZLI in mild lung disease and for PA eradication.     

Adalimumab: in psoriatic arthritis

Adalimumab, a fully human monoclonal antibody, is a tumour necrosis factor antagonist that has been investigated for efficacy in psoriatic arthritis, based on well-established use of the drug in rheumatoid arthritis. In well-controlled Phase III trials, adalimumab (40 mg administered subcutaneously every other week) has shown efficacy in adult patients with psoriatic arthritis who had an inadequate response to previous treatment with NSAIDs (24-week ADEPT trial; n = 313) or disease-modifying antirheumatic drugs (12-week study; n = 100). In these trials, adalimumab recipients experienced a significantly greater improvement in arthritis response (p < 0.001 in the ADEPT trial, and p 相似文献   

Insulin aspart : an evidence-based medicine review

This paper provides a review and evaluation of the published evidence relating to the efficacy, safety and ease of administration of the rapid-acting insulin analogue insulin aspart in comparison with human insulin (HI) in diabetes mellitus in the following categories: (a) in adults, (b) in children, and (c) in continuous subcutaneous insulin infusion (CSII). A search for publications on insulin aspart was conducted for the following databases: Cochrane, BIOSIS, EMBASE-DP and MEDLINE. Publications were examined for relevance by two independent assessors and were graded using a system developed by the Oxford Centre for Evidence-Based Medicine. Overall, the evidence comparing insulin aspart with HI was of high quality, with all three categories graded as grade A evidence. Studies showed strong evidence for better glycaemic control, without an increased risk of hypoglycaemia, together with evidence supporting improved convenience and flexibility in administration of insulin aspart compared with regular HI in adult diabetic patients. Evidence from three trials in adults with type 1 diabetes showed a lower incidence of major nocturnal hypoglycaemia with insulin aspart versus regular HI. Published evidence also confirmed the more rapid action of insulin aspart versus HI, and a comparable efficacy and safety profile for both insulin types in type 1 paediatric patients. There was also strong evidence that insulin aspart is well tolerated and efficacious for CSII/pump use. Insulin aspart better mimics the physiological response to meals than regular HI, and may offer advantages in terms of glycaemic control and reduction of hypoglycaemia combined with flexibility and convenience of administration. Overall, there is a good body of evidence to support the efficacy, tolerability and ease of administration of insulin aspart in patients with type 1 and type 2 diabetes.     

Emerging drugs for psoriatic arthritis

Introduction: The majority of Psoriatic Arthritis patients experience a good clinical response to anti-Tumor Necrosis Factor (TNF)-α therapies. However, treatment failure with anti-TNF-α can represent a relevant clinical problem.

Areas covered: We review the efficacy and safety profile of biological therapies that have been reported from randomized, controlled trials in phase II and phase III available in Pubmed Database for agents targeting IL-12/23p40 antibody (ustekinumab) and IL-17 (secukinumab), inhibitor of phosphodiesterase 4, (apremilast), and of JAK/STAT pathways (tofacitinib) and CTLA4 co-stimulation (abatacept) in Psoriatic Arthritis.

Expert opinion: In Psoriatic Arthritis, main emerging drugs are represented by the fully human monoclonal IL-12/23p40 antibody, ustekinumab, the agent targeting IL-17, secukinumab, and the inhibitor of phosphodiesterase 4, apremilast.

Results on T cell co-stimulation inhibition by abatacept are insufficient both in psoriasis and in PsA. In vitro investigations on JAK/STAT pathways in PsA suggest that tofacitinib could represent a further valuable therapeutic option.

Emerging biological treatments other than anti-TNF agents, ustekinumab, secukinumab and apremilast appear promising for Psoriatic Arthritis and recent studies have showed a good efficacy and an acceptable safety profile; however, further and long-term studies are advocated.     

Acute postoperative hypertension: a review of therapeutic options.

PURPOSE: The pathophysiology and treatment of acute postoperative hypertension (APH) are discussed. SUMMARY: APH is a significant elevation in arterial blood pressure (BP) during the immediate postoperative period. The predominant underlying mechanism appears to be sympathetic activation. APH may lead to serious neurologic, cardiovascular, or surgical-site complications and often requires intervention and management. Postoperative hypertension lasts less than six hours in most patients. Reversible or treatable causes of hypertension, including pain, anxiety, hypothermia, and hypoxemia, should be considered and treated before the implementation of antihypertensive therapy. The ideal agent for treating APH is intravenously administered, is fast acting, and has a short duration of action, allowing the rapid and safe adjustment of therapy to achieve a targeted BP range. Sodium nitroprusside has long been considered the standard therapy and has many of the ideal characteristics. However, because of the need for invasive hemodynamic monitoring and concerns about toxicity in patients given sodium nitroprusside, several newer agents may be preferable in routine clinical practice. Labetalol, nicardipine, and nitroglycerin have been widely studied or used. Hydralazine, esmolol, fenoldopam, angiotensin-converting-enzyme inhibitors, and clonidine may also be useful treatment options. CONCLUSION: When treatment of APH is necessary, therapy should be individualized for the patient. No one agent is preferred, but effective options include sodium nitroprusside, nitroglycerin, labetalol, and nicardipine.     

Ustekinumab: a review in the treatment of plaque psoriasis and psoriatic arthritis

Psoriasis is a complex, multigenic immune/inflammatory-mediated disorder that variably affects the skin, nails, and joints. In September 2009, ustekinumab (Stelara?), a monoclonal antibody that targets interleukin 12 (IL-12) and 23 (IL-23), was approved in the United States for treatment of moderate-to-severe plaque psoriasis. The drug's mechanism of action is derived from extensive immunologic and genomic research identifying IL-12 and IL-23 of the Th1 and Th17 inflammatory pathways, respectively, as key mediators of psoriasis. Ustekinumab is a completely human monoclonal antibody to the shared p40 subunit of IL-12 and IL-23. The drug has demonstrated efficacy, short-term safety, and convenience of use in the treatment of plaque psoriasis and psoriatic arthritis. Though long-term safety concerns remain, ustekinumab adds to the current treatment armamentarium and holds promise to improve quality of life. This is a concise and current review of ustekinumab in the treatment of plaque psoriasis and psoriatic arthritis, with focus on data from the seven published clinical trials.     

Hypertension in the elderly: an evidence-based review

The progressive ageing of world population, and the increasing prevalence hypertension in elderly people are leading to the consideration that hypertension in the elderly is one of the main topic in hypertension treatment. Multiple mechanisms, including stiffening of large arteries, endothelial dysfunction, cardiac remodeling, autonomic dysregulation, renal aspects, contribute to the great prevalence of hypertension in the elderly and to increased cardiovascular morbidity and mortality. Treatment of hypertension can hardly put back older patients in a low risk category, especially if target organ damage is present. Nevertheless, blood pressure control can successfully prevent stroke, cognitive decline, coronary heart disease and heart failure, and reduce mortality in the elderly, and even in patients > 80 years, as recently demonstrated. Blood pressure should be lowered below 140/90 mmHg also in older patients. However the HYVET study suggests that a goal of 150/90 mmHg can be reasonable in patients aged 80 years or more. Drug treatment should be titrated with particular caution to adverse responses and excessive blood pressure lowering.     

Treatment strategies for early psoriatic arthritis

Background: Until a few years ago, the early diagnosis of psoriatic arthritis (PsA) did not receive much attention, especially in view of the lack of drugs capable of altering the disease course. This changed with the introduction of the TNF-α-blocking agents, as a result of which the early diagnosis of PsA is now a topic of great interest. Objective: The aim of the study was to review the treatment for PsA in order to determine the optimal approach to managing early disease. Methods: The systematic review performed by members of GRAPPA (Group of Research and Assessment of Psoriasis and Psoriatic Arthritis) was integrated with data from more recent studies. Results/conclusion: After making the diagnosis of PsA, the next step is to stage of the disease with the aim of establishing the prevalent manifestation (peripheral arthritis, peripheral enthesitis, axial involvement and dactylitis) and degree of severity (mild, moderate or severe) of the disease. Each patient should be treated according to the defined disease status following the suggested treatment algorithms.     

Drug removal by plasmapheresis: an evidence-based review

Contrary to the literature about drug removal during hemodialysis, data regarding drug removal during plasmapheresis are sparse. Over the last 40 years, approximately 70 publications-mostly case reports of overdoses-have described the effects of plasmapheresis on pharmaceutical agents. Important issues are drug extraction during plasma exchange with chemotherapy, as well as drug classes such as antiinfectives, anticoagulants, antiepileptics, cardiovascular agents, and immunosuppressants. Other considerations are the merits and pitfalls of the different methods used in published reports and recommendations for future pharmacokinetic studies in this field.     

Drug-induced psoriasis: an evidence-based overview and the introduction of psoriatic drug eruption probability score

Psoriasis is a common skin disorder that needs a long-term management, not only because, of its prevalence but also because of the profound impact it can have on patients quality of life. Drugs may result in exacerbation of a preexisting psoriasis, in induction of psoriatic lesions on clinically uninvolved skin in patients with psoriasis, or in precipitation of the disease in persons without family history of psoriasis or in predisposed individuals. The knowledge of the drugs that may induce, trigger, or exacerbate the disease is of primary importance in clinical practice. By reviewing the literature, there are many reports on drug-induced psoriasis, but the data are not univocal. We propose, when possible, the use of a probability score from the authors to obtain a better classification and further understanding of drug-induced psoriasis.     

Sevelamer as a phosphate binder in adult hemodialysis patients: an evidence-based review of its therapeutic value

INTRODUCTION: Patients on hemodialysis require phosphate binders to reduce dietary phosphate absorption and control serum phosphate. The standard therapy, calcium salts, can be associated with elevated serum calcium (hypercalcemia). Concern has been raised that hypercalcemia, especially combined with elevated serum phosphate, may be associated with arterial calcification, and this may contribute to increased risk of cardiovascular mortality and morbidity. Sevelamer is a nonmetal, nonabsorbed phosphate binder. AIMS: This review assesses the evidence for the therapeutic value of sevelamer as a phosphate binder in adult hemodialysis patients. EVIDENCE REVIEW: Strong evidence shows that sevelamer is as effective as calcium salts in controlling serum phosphate and calcium-phosphate product, has less risk of inducing hypercalcemia and is more effective at lowering lipid levels. Some evidence indicates that sevelamer reduces arterial calcification progression and loss of bone mineral density, but it may be more likely to induce metabolic acidosis, compared with calcium salts. Sevelamer-containing regimens may improve calcific uremic arteriolopathy, although the evidence is weak. Evidence is divided on whether the incidence of gastrointestinal adverse events with sevelamer is similar to or higher than that with calcium salts. Retrospective and modeling studies suggest lower cardiovascular morbidity and mortality with sevelamer than with calcium salts, with incremental cost-effectiveness of $US1100-2200 per life-year gained. Further direct evidence is needed on mortality, quality of life, and cost-effectiveness. PLACE IN THERAPY: Sevelamer is effective in controlling serum phosphate and lowering lipid levels in hemodialysis patients without inducing hypercalcemia, and may have beneficial effects on arterial calcification.