Abstract Diabetes mellitus is a common metabolic disorder characterized by high blood glucose levels resulting from an insulin deficiency (type 1 diabetes mellitus) or a combination of insulin deficiency and insulin resistance (type 2 diabetes mellitus). The chronic hyperglycemia associated with diabetes mellitus can cause damage to the eyes, kidneys, heart and peripheral circulation, resulting in substantial morbidity, premature mortality and considerable healthcare costs. In both type 1 and type 2 diabetes mellitus, quality of glycemic control has been shown to be a major factor in the prevention of microvascular complications, and tight blood glucose control is the primary goal for all patients with diabetes mellitus. In patients with type 1 diabetes mellitus, multiple daily injections of exogenous insulin and frequent monitoring of blood glucose levels are required to achieve tight glycemic control. Patients with type 2 diabetes mellitus may achieve initial glycemic control with diet and lifestyle interventions alone; however, a large percentage of patients will require pharmacological therapy, first with an oral antidiabetic agent and, ultimately, with insulin. Premixed insulin formulations, consisting of fixed ratios of short- and intermediate-acting insulins, are a convenient and effective treatment option which account for ≈40% of insulin use worldwide. Until recently, the only premixed formulations available contained varying proportions of human regular insulin and human isophane insulin suspension (NPH). However, new premixed formulations containing insulin lispro (a rapid-acting insulin analog) and insulin lispro neutral protamine suspension (NPL) [an intermediate-acting insulin analog] are now available. Insulin lispro mix75/25 (Humalog® Mix75/25™) is a premixed formulation containing 25% insulin lispro and 75% NPL which has been investigated for use in patients with type 1 and with type 2 diabetes mellitus. Administered twice daily immediately before breakfast and dinner, insulin lispro mix75/25 provides better control of postprandial blood glucose, provides similar overall glycemic control, appears to be preferred by patients and may reduce nocturnal hypoglycemia compared with a similar premixed formulation containing 30% human regular insulin and 70% NPH (human insulin 70/30; Humulin® 70/30, Novolin® 70/30). Insulin lispro mix75/25 has a rapid onset of action, allowing for administration immediately before a meal, whereas patients need to administer human insulin 70/30 30 to 60 minutes prior to meals. Insulin lispro mix75/25 also improves glycemic control in patients whose type 2 diabetes mellitus is not well controlled by oral agents. Conclusion Insulin lispro mix75/25 is suitable for patients wishing to use premixed insulin formulations and may offer several benefits over human insulin 70/30.
Summary Disease management strategies, which seek to integrate care around the needs of various stakeholders — providers, drug and device makers, physicians, patients, managed care organisations and employers — have the potential to markedly change how healthcare services are delivered. To support this transition, information technologies are needed to facilitate the collection, integration, analysis, real-time presentation and secure storage of clinical data. This article reviews the needs of the various stakeholders in disease management and links these needs to healthcare delivery information technologies, both currently existing and planned. It summarises the status of the core information technologies that support healthcare delivery and disease management. The article focuses on the principles of evaluating the costs and benefits of information technology with respect to the business plan for the clinical organisation and of successfully implementing information technology in the healthcare setting.
Pharmacists are in an ideal position to assess, monitor and treat adherence-related problems that can adversely affect patients’ health outcomes. To accomplish these goals, pharmacists must accept the responsibilities and challenges of a primary care provider. They also must assume an interdisciplinary role in collaborative drug therapy management. Strategies to monitor and improve adherence are key components of pharmaceutical care plans, especially for patients with chronic diseases, such as hypertension, diabetes mellitus and atherosclerotic heart disease. This article gives an overview of guidelines, recommendations, current practices and related issues in the management of patients with diabetes mellitus. It also reviews the behavioral and social factors that influence adherence to therapeutic and lifestyle regimens, and highlights special needs in selected high-risk populations. Finally, best practice strategies that could serve as appropriate models for pharmaceutical care services are discussed. The overall goal is to enhance pharmacists’ professional abilities to coordinate pharmaceutical care services targeted for major modifiable behavioral and biological risk factors. Pharmacists can overcome their apprehension about undertaking a primary care role in diabetes management through adequate preparation (including training and certification). The primary care functions that have been evaluated to date in the care of patients with diabetes mellitus by pharmacists show successful patient outcomes in terms of cost, quality of life and reduction of complications.
Heart failure (HF) is a complex syndrome characterized by the inability of the heart to maintain a normal cardiac output without elevated intracardiac filling pressures, resulting in signs of pulmonary and peripheral edema and symptoms of dyspnea and fatigue. Central to the management of HF is a multifaceted pharmacological intervention to abate the harmful counter-regulatory effects of neurohormonal activation and avid salt and water retention. Whereas up to 40 years ago HF was managed with diuretics and leaf of digitalis, the cornerstones of therapy for HF patients with systolic dysfunction now include ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers), β-adrenoceptor antagonists (β-blockers), and aldosterone antagonists, which have significantly improved survival. However, with the increasing number of beneficial therapies, there are challenges to implementing all of them. Specific cardiomyopathies also merit specific considerations with respect to treatment, and — unfortunately — there is no therapy for HF with preserved left ventricular ejection fraction that has been shown to improve survival. Although mortality has improved in HF, the biggest challenge to treatment lies in addressing the morbidity of this disease, which is now the most common reason for hospital admission in our aged population. As such, there are many therapies that may serve to improve the quality of life of HF patients. Future HF treatment regimens may include direct cellular therapy via hormone and cytokine signaling or cardiac regeneration through growth factors or cell therapy.
Case management is an evolving healthcare process and role. Confusion about the definition and scope of case management has arisen because of the diversity of ways the role has been implemented and the changing healthcare landscape within which case managers function. From its early heritage in coordination of care and advocacy for the vulnerable, case management developed to meet the demands of a growing and changing health system. The focus on the individual has expanded to encompass management of the patient and the system of care. The advent of managed care has transformed the role of the case manager toward population- and outcome-based care. The next era will focus on longitudinal, comprehensive and integrated Wellness, disease and illness management.
Summary Although it may seem odd to medical professionals to state that disease management is a new concept, it represents a sea change in medical care delivery. Because of the dramatic increases in technologies that do not cure diseases, but improve them, and the costs we pay for using these technologies, we are finding that medical delivery models based on cure are no longer viable. Evidence for better strategies that coordinate care across populations of persons with similar diseases is at hand. As financial pressures mount, organised approaches to disease management will become more widespread. Along the way, the existing Roles of key players, such as hospitals, physicians and pharmaceutical companies, will change.
Barrett’s esophagus is a condition that develops in approximately 10–15% of patients with chronic gastroesophageal reflux disease and is the only known major risk factor for esophageal adenocarcinoma. The incidence of esophageal adenocarcinoma has increased by 350% over the last 3 decades and the reasons for this dramatic increase are unclear. At the time of cancer diagnosis up to 50% of patients will have advanced regional or distant metastatic disease, with little or no chance of cure. The overall 5-year survival rate with advanced disease remains poor at <10%. Several studies have demonstrated an early stage of diagnosis and a marked improvement in the survival of patients with esophageal cancer detected by routine endoscopic surveillance in patients known to have pre-existing Barrett’s esophagus. The aim of endoscopic surveillance in patients with Barrett’s esophagus is the early diagnosis of esophageal cancer, when it is still potentially curable. The desired outcome is to further decrease the mortality rate associated with esophageal adenocarcinoma and identify and screen populations at risk for the development of dysplasia arising from Barrett’s esophagus. This is the principle of the current screening and surveillance guidelines set out by several societies, including the American College of Gastroenterology, the American Society of Gastrointestinal Endoscopy, and the European Society of Gastrointestinal Endoscopy. However, as most patients with Barrett’s esophagus do not develop adenocarcinoma, the cost effectiveness of endoscopie screening and surveillance strategies is questionable. To date, no prospective, randomized trials have been performed to evaluate the effectiveness of surveillance, the survival benefit in patients undergoing surveillance or the subsequent impact on healthcare costs. In this article, we focus on the basic principles and reasoning underlying the surveillance guidelines for Barrett’s esophagus. In particular, that the disease is clinically important and has a high prevalence; the transition to adenocarcinoma could have a high death and/or disability rate; early diagnosis of adenocarcinoma should reduce mortality; and the screening method should be easily applied, safe, relatively inexpensive, and applicable to a large number of patients. We then review arguments for and against screening and surveillance as they apply to these principles and discuss the current literature that reviews the effectiveness of such surveillance strategies, including an outline of cost analysis.
Summary This article reviews the early experience of organisations in the US who have attempted to design, develop and implement disease management programmes. A systems approach is recommended and outlined as a solution to the obstacles that have hindered the success of ‘first generation’ disease management programmes. The authors focus on important considerations and specific components needed to build a solid foundation for the successful implementation of disease management systems.
There is growing consensus that a major obstacle to good outcomes among individuals with bipolar disorder (BPD) is premature discontinuation of medications. This review summarizes the current literature on prevalence and consequences of non-adherence in BPD populations, measurement of adherence, risk factors for non-adherence, and general and psychoeducational interventions to enhance treatment adherence among bipolar populations, and suggests future directions in psychoeducational approaches with respect to treatment adherence. Risks associated with discontinuation of medication among individuals with BPD are well documented and include manic and depressive relapses, re-hospitalization, and more lengthy hospital stays. A relatively limited but growing literature suggests that it is possible to enhance treatment adherence among patients with BPD. The most positive evidence for the improvement of medication adherence among patients with BPD comes from specific psychosocial interventions used in conjunction with pharmacotherapies. It has been suggested that improved treatment adherence is at least a partial component of the observed positive outcomes of psychoeducational approaches among bipolar populations. Many individuals with BPD remain relatively uninformed regarding their illness, creating potential barriers to optimal treatment adherence, and limiting self-management skills. Psychoeducation is based on the premise that individuals have a fundamental right to have information regarding their illness, and individuals who are informed are more likely to take a more active role in managing their illness, which results in better health outcomes. Psychoeducation strategies for BPD that have contributed to positive outcomes have ranged from simple one-site, education-only interventions that improve lithium adherence and attitudes about medications to a more complex, multi-site, collaborative care system intervention that yielded shorter durations of affective episodes for patients, improved functioning and quality of life, and treatment satisfaction. Although psychological therapies that emphasize psychoeducation generally support benefits in achieving and maintaining remission from bipolar symptoms, the effects of these interventions on treatment adherence are not consistent and the way in which psychoeducation improves outcomes is not entirely clear. There is an urgent need for greater understanding of interventions that can be implemented in real-world settings that address patient, provider/system, and environmental/social factors that are critical to treatment adherence.
Smoking accounts for significant morbidity and mortality and has major economic consequences for healthcare delivery throughout the world. Government policy such as increasing taxes and restricting advertising go some way to reduce smoking, but the social and economic factors that affect target populations will impact on the success of any strategy. Public health interventions can also contribute to increasing cessation rates. The most successful interventions appear to be those characterised by personalised advice and assistance, repeated in different forms over the longest feasible period of time. Pharmacological aids, which are important components of a cessation programme, include nicotine replacement therapy in the form of chewing gum, patches, nasal spray, oral inhaler or sublingual tablets; bupropion (amfebutamone) has been approved for use in some countries. As the community pharmacy is the major point of supply of such products, the pharmacist is in a key position to encourage and support clients who wish to stop smoking. A number of studies have examined the role of the community pharmacist in assisting smokers through the so-called ‘cycle of change’. These studies have utilised a model that offers individualised advice through a motivational technique to encourage a change in behaviour; nicotine replacement therapy is optional. Follow-up is an essential part of these programmes to monitor progress and to provide additional support. Evaluations of these pharmacy-based initiatives have confirmed the importance of a multifaceted approach in achieving success in smoking cessation, i.e. behaviour modification, nicotine replacement therapy and client support.
Résumé Au niveau mondial, la prévalence du diabète de type 2, non insulino-dépendant, varie de 1% en Afrique à 4% en Amérique du Nord, représentant au total, en 1997, près de 120 millions de diabétiques de type 2. En Asie, si la Chine a des taux de prévalence particulièrement bas à 1,1%, Hong Kong a par contre une fréquence de diabète de type 2 de 5,6% et le Japon, pays à espérance de vie élevée, un taux de 4,9%. En Europe, les prévalences du diabète non insulino-dépendant varient beaucoup avec 2,4% en Europe du Nord, 2,8% en Europe de l’Ouest, 2,5% en Europe de l’Est et 4,1% en Europe du Sud. On peut estimer à un peu plus de 21 millions le nombre de diabétiques de type 2 en Europe. Ce chiffre pourrait atteindre au niveau mondial 215 millions en 2010. Les différences de prévalence peuvent s’expliquer par les variations d’espérance de vie, d’environnement, de mode de vie et enfin, de patrimoine génétique. Le diabète recouvre en réalité deux maladies: le diabète insulino-dépendant souvent du sujet jeune (type 1), 10 à 20% des diabétiques, et le diabète non insulino-dépendant (type 2), 80 à 90% des diabétiques, qui touche le plus souvent les individus à partir de la cinquantaine. Le diagnostic de diabète ne pose pas de problème lorsque l’hyperglycémie est franche et constante. Il est plus difficile pour les valeurs frontières. Des critères américains récents ont abaissé le seuil de la glycémie à jeun à partir duquel le sujet peut être considéré comme diabétique (7,0 mmol/L ou 1,26 g/L en deux occasions). La variabilité de la glycémie qui définit le diabète s’ajoute aux difficultés pathogéniques de cette maladie où s’intriquent facteurs génétiques et environnement. Le rôle de l’hérédité a été confirmé par les avancées importantes de l’analyse génétique et repose sur un mode de transmission polygénique. D’autres marqueurs déterminés a priori interviennent, comme le poids de naissance et l’âge, sur lesquels il est “difficile” d’agir. A côté de ces éléments, il existe des facteurs de risque liés à l’environnement et au comportement, bien mis en évidence par les études des migrants. Le rôle de l’obésité et son ancienneté, est reconnu depuis longtemps, plus précisément le lien entre répartition abdominale des graisses et diabète non insulino-dépendant, comme associé à des anomalies métaboliques en rapport avec une insulinorésistance, pouvant s’inscrire dans le cadre du syndrome X. Tous ces facteurs se combinent à divers degrés pour aboutir à une intolérance au glucose puis au diabète non insulino-dépendant. Les attitudes comporte-mentales, aussi bien sur le plan alimentaire que sur celui de l’activité physique, peuvent avoir une grande influence sur cette évolution. Longtemps asymptomatique, le diabète de type 2 est souvent découvert tard dans son évolution, parfois en présence de complications. L’évolution et le pro-nostic du diabète de type 2 sont dominés par les complications micro et macro-vasculaires qui lui sont associées. Ce sont essentiellement, pour les atteintes microvasculaires, la rétinopathie (avec une prévalence de 20 à 50%), la néphropathie (20 à 42%), la neuropathie (10 à 45%). L’atteinte des gros vaisseaux est responsable de 75% des décès des diabétiques. Elle concerne surtout les vaisseaux du cœur, (prévalence de 5 à 44%) et ceux des membres inférieurs (1 à 14%), puis à un moindre degré, ceux du cerveau. Les maladies cardiovasculaires représentent les complications les plus fréquentes du diabète de type 2, entraînant 2 à 3 fois plus de décès que chez les non diabétiques. Il faut également noter que les taux de décès toutes causes con-fondues, sont multipliés au moins par 2 chez les diabétiques par rapport aux non diabétiques. La gravité de cette maladie provient de ses complications, essentiellement micro et macrovasculaires, alors que de simples mesures de prévention hygiéno-diététiques pourraient être prises très tôt pour éviter son développement et son aggravation.
The effective management of chronic illness has historically been plagued by patient non-adherence to treatment regimens. While disease management initiatives have recently proliferated in an attempt to more effectively manage these chronic illnesses, many of these new programmes have lacked effective behaviour change interventions. It is expected that this void will hopefully be corrected as more sophisticated second generation disease management programmes are developed. This article explores the major issues and forces driving patient non-adherence and recommends a number of strategies to be used to enhance patient adherence and to improve patient self-management. Specifically, the authors propose 6 guiding principles for improving patient adherence and self-management. These principles include: (i) taking a comprehensive, holistic, patient-centred approach to disease management; (ii) being aware of the many different forms of nonadherence; (iii) facilitation of patient motivation and readiness to change; (iv) collaboratively supporting self-management behaviour; (v) focusing less on problems and more on solutions; and (vi) establishing and maintaining good communications with the patient. The success of disease management will require, in many cases, a major reengineering of how we deliver and coordinate healthcare. Importantly, the development of systematic behaviour change interventions and adoption of a true patient-centred approach to disease management will be essential if meaningful, long term clinical and economic outcomes are to be achieved. Case managers and specialty disease management organisations that focus on the development of new, implementable behaviour change interventions will play a major role in insuring that our second generation of disease management programmes incorporate these new patient empowerment interventions.
Cardiac rehabilitation has been shown to improve exercise tolerance and symptomatology in patients experiencing angina or heart failure and reduce long term mortality after myocardial infarction, with a good cost-effectiveness ratio. In addition to these ‘hard’ endpoints, cardiac rehabilitation improves the patient’s quality of life and risk factor profile through a multifactorial intervention. Indeed, cardiac rehabilitation is no longer restricted to physical reconditioning, but should now be understood as the long term care of cardiac patients through a personalised and periodically updated programme. The components of a comprehensive cardiac rehabilitation programme should comprise risk stratification of the patient, physical reconditioning programmes, secondary prevention and vocational counselling. This article is a synthesis of the principal guidelines and recently published recommendations on cardiac rehabilitation. It focuses on the practical modalities of a cardiac rehabilitation programme, the setting up of the multidisciplinary team, the different facilities according to local possibilities and the patient’s clinical status, the prescription of a personalised programme, safety measures and emergency procedures. Together with these general considerations, special populations which constitute new but growing indications for cardiac rehabilitation are addressed: patients with heart failure, elderly patients and women, who need specific management. In the future, cardiac rehabilitation should be characterised by a likely increase in its indications because of: (i) a predicted high prevalence of coronary artery disease (due to an aging population and an improvement in survival after a cardiac event) despite a lower mortality rate; and (ii) an expansion of the indications in both low and high risk patients. In low risk patients, the goals of cardiac rehabilitation will be to prevent further progression of coronary atheroma and preserve ventricular function by preventive measures such as lifestyle and medical treatment. The needs of high risk patients (who are essentially heart failure patients) are the restoration of autonomy, when lost, and a better quality of life through the improvement of exercise capacity: those patients who were formerly excluded from cardiac rehabilitation programmes are in fact those who are now deriving the greatest benefit from exercise training. Owing to the proven benefits of this new concept of the multifactorial approach, cardiac rehabilitation has, nowadays, become an integral part of the treatment of cardiac patients.
Summary Congestive heart failure (CHF), a state of abnormal cardiac function, is a common end-stage of heart disease, greatly shortening survival. In the US, as in many countries, it is an increasingly major burden on families and the healthcare system. Nearly 5 million people have CHF, it is the leading diagnosis in hospitalisations of persons aged 65 years and over, 13% of all deaths in 1993 had CHF mentioned on the death certificate, and healthcare expenditures amounted to $US17.5 billion in 1993. Prevalence, mortality, hospitalisations and visits to physicians for CHF are increasing. They are expected to continue increasing as the numbers of older persons in the population increase and as survival following coronary heart disease continues to improve. In a community cohort study, median survival following initial CHF was only 1.7 years in men and 3.2 years in women. The risk of CHF depends on a person’s status with respect to predisposing diseases and risk factors. Hypertension, which is present in 50 million people, carries the largest attributable risk of CHF. Myocardial infarction carries the next highest attributable risk, followed by diabetes. Means for early detection and control of hypertension and myocardial infarction have been proven effective, however, they are not being fully utilised. The goal should be to prevent or limit myocardial damage before CHF ensues. Using ordinary office procedures, high risk candidates for CHF can be detected before overt manifestations present. Treatment of hypertension and left ventricular dysfunction can decrease incidence of CHF, and use of ACE inhibitors or vasodilators can prolong survival.
Summary The treatment of rheumatoid arthritis (RA) has always been a challenge. In the last 5 years, many leaders in the field have emphasised the potential of early and aggressive therapy either with single or multiple slow-acting antirheumatic drugs (SAARDs). Single agents, if given early enough, may slow the radiological progression, but many feel that combination therapy with different SAARDs and corticosteroids are more likely to achieve clinically important reduction in the progression of joint destruction and disability. Combining drugs with different toxicities or using lower doses of toxic drugs in combination may decrease the risks associated with SAARDs while maintaining or increasing the efficacy. Few well-designed clinical trials have been undertaken to test the usefulness of combination therapy. The role and dosage of corticosteroid therapy continue to be debated. In most parts of the world, corticosteroids have been reserved for patients with more severe disease. However, they are commonly used earlier in the US in combination with other SAARDS, especially before the patient begins a new SAARD. This review is a qualitative overview of the literature in MEDLINE using the standardised approach recommended by the Cochrane Collaboration supplemented by contacting investigators active in the area to assess the existing evidence.
Summary Epilepsy is a common condition with multiple potential causes that may present as a variety of types of seizure. Drug therapy is the mainstay of treatment, with seizures being controlled by monotherapy in approximately 60% of patients. In a minority of patients, seizures are controlled by combinations of antiepileptic drugs. Approximately 20% of patients have treatment-resistant epilepsy which, in some cases, will respond to surgical treatment. The management of epilepsy with drugs requires a clear diagnosis of the type of epilepsy. One or several individual drugs are then tested initially as monotherapy and in combination if necessary until efficacy is established. The use of older drugs (e.g. phenytoin, carbamazepine, etc.) is generally well established in the treatment of different types of epilepsy. Although other agents have their place, valproic acid (sodium valproate) appears to be the only agent with a sufficiently broad spectrum of activity to allow its use in all types of epilepsy. Valproic acid and carbamazepine are often used as first-line treatment for patients with partial epilepsy. However, adverse effects or drug interactions often dictate the choice between older antiepileptic drugs. In assessing newer agents, differences in efficacy, tolerability, drug interactions and contraindications often make treatment choices clear. Furthermore, several newer drugs are licensed only for add-on therapy, which restricts their use. Lamotrigine is a newer antiepileptic drug with efficacy in most seizure types. It has been demonstrated to be effective and well tolerated when added to established antiepileptic drug regimens in adults and children, and as monotherapy in adults. Although it must be introduced slowly to minimise the possibility of skin rash, once at maintenance dosages it may be administered once or twice daily. The tolerability and drug interaction profiles of lamotrigine are well characterised. Thus, lamotrigine provides an effective and generally well tolerated alternative to older and newer antiepileptic drugs in the treatment of a variety of types of epilepsy.
Summary Disease management is a systematic population-based approach to identifying those at risk, intervening using information from the growing field of evidence-based medicine, and measuring patient outcomes once an intervention is in effect. Operationally, this is a challenging series of tasks, and a vulnerability for this field. Important aspects include the development of clear clinical guidelines, agreement on the part of providers and patients to participate, a sophisticated information architecture, well-designed and tested interventions and a logical measurement plan for the collection of outcomes. While there is a clear need for evidence of its benefit, the field is expanding rapidly and incorporating many other disciplines and aspects of healthcare delivery as well.
Summary Evidence-based medicine is the process of finding and applying the best available clinical research evidence to the management of individual patients. This first requires posing an appropriate answerable clinical question about diagnostic possibilities, prognosis, risks, diagnostic tests or treatment. We then need to rapidly and efficiently identify the best clinical research evidence to answer these questions. This may involve using either ‘predigested’ sources of evidence, such as systematic reviews or evidence-based guidelines, or, when these are not available, finding the primary evidence ourselves. Finally, this research evidence needs to be weighed, appraised and integrated with our clinical expertise to apply it to the individual patient problem. Recent studies have suggested that 82% of treatment decisions in a general medical ward and 69% of decisions in ambulatory care can be based on convincing evidence, more than half of which comes from randomised controlled trials. The key problem then is finding and integrating such evidence into routine practice. The recently established Cochrane Collaboration is beginning to provide a systematic summary of randomised trial evidence of the effects of treatment, but will take 5 to 10 years to provide comprehensive coverage. However, a number of other summary sources, together with skills in using ‘Medline’ efficiently and effectively, will provide practitioners with ready access to the best evidence. We illustrate these methods with several cases from ambulatory practice.
Rheumatoid arthritis is a progressive, disabling disease which can lead to long-term deformity and disability. Leflunomide is a disease-modifying antirheumatic drug (DMARD) approved to reduce signs and symptoms, inhibit structural damage and improve physical function in adults with active rheumatoid arthritis. In clinical trials in patients with active rheumatoid arthritis, leflunomide had a more rapid onset of action than methotrexate, sulfasalazine and placebo. In trials of 24 months’ duration, leflunomide was more effective than sulfasalazine and placebo and at least as effective as methotrexate in reducing rheumatoid arthritis disease activity (assessed using the American College of Rheumatology [ACR] criteria). In addition, leflunomide was as effective as sulfasalazine or methotrexate in decreasing the rate of radiological progression over 24 months. Over 12 months leflunomide was more effective than methotrexate and placebo in reducing the rate of structural damage. Data from a nonblind extension study suggests that the efficacy of leflunomide may be maintained when administered for periods up to 5 years. Leflunomide was significantly more effective than methotrexate, sulfasalazine and placebo in improving physical function measures among patients with active rheumatoid arthritis, and improved physical function was maintained after 2 years of treatment. Few well designed pharmacoeconomic analyses of leflunomide treatment in patients with rheumatoid arthritis exist. Economic studies to date show leflunomide to be either less cost effective or cost neutral compared to methotrexate. In addition, leflunomide has been shown to be a cost effective option compared with etanercept, infliximab and infliximab plus methotrexate. Leflunomide was generally well tolerated in clinical trials. Common adverse events associated with leflunomide treatment include diarrhea, respiratory infections, nausea and headache. Hematological and hepatotoxic adverse events are a concern, particularly in a setting of multiple risk factors such as concomitant hepatotoxins. Liver function monitoring should be adhered to in all patients receiving leflunomide and ACR guidelines should be followed in those receiving concomitant methotrexate. In conclusion, leflunomide is a DMARD which produces a rapid and sustained reduction in disease activity in patients with active rheumatoid arthritis. Leflunomide has a more rapid onset of action than sulfasalazine or methotrexate. Leflunomide is at least as effective as methotrexate and more effective than sulfasalazine in reducing disease activity after 24 months’ treatment. In addition, leflunomide is more effective than both of these agents in improving physical function and health-related quality of life. Thus it is predicted that leflunomide therapy may improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial burden imposed by the disease for patient, healthcare provider and payers. Consequently, leflunomide should be considered as an important treatment option for those patients with active rheumatoid arthritis including those intolerant to methotrexate.
Rheumatoid arthritis is associated with substantial costs to both the individual and society; costs increase as disease severity worsens. Current thinking is that disease-modifying antirheumatic drug (DMARD) therapy should be started as soon as possible after the diagnosis of rheumatoid arthritis and that patients should be offered the most effective treatment available. Etanercept is a soluble dimeric fusion protein comprising two copies of the extracellular ligand-binding domain of the human p75 receptor for tumour necrosis factor-α (TNFα) linked to the constant portion of human immunoglobulin G1. TNFα is thought to play an important role in the pathophysiology of rheumatoid arthritis; by binding the cytokine, etanercept blocks its biologic effects. In a 12-month double-blind, randomized study involving patients with early active rheumatoid arthritis, administration of subcutaneous etanercept 25mg twice weekly was associated with a more rapid and significantly greater overall response (assessed using American College of Rheumatology criteria) than oral methotrexate. In addition, compared with methotrexate, etanercept was associated with more rapid slowing of radiographic progression and a more rapid improvement in measures of health-related quality of life. The efficacy of etanercept was maintained at 3 years’ follow-up. Etanercept, alone or in combination with methotrexate, also showed sustained efficacy in three double-blind, randomized, placebo-controlled studies of 3 to 6 months’ duration involving patients with active rheumatoid arthritis who had not responded adequately to previous treatment with DMARDs. Etanercept was generally well tolerated in clinical trials (the most commonly occurring adverse events included injection site reactions, infection, headache, nausea, rhinitis, dizziness, pharyngitis and cough). The high cost of etanercept relative to traditional DMARDs may be justified if it can be shown to reduce long-term outcomes associated with rheumatoid arthritis, thereby reducing disease costs. Conclusion: Etanercept is an important new treatment option in rheumatoid arthritis. It provides a rapid and sustained reduction in disease activity and inhibits the progression of structural damage in patients with early active rheumatoid arthritis, with good tolerability. The improvement in disease activity and slowing of joint damage seen with etanercept was more rapid than that seen with methotrexate. In addition, etanercept, alone or in combination with methotrexate, is effective in the treatment of patients with active rheumatoid arthritis who have not responded adequately to previous DMARD therapy. It is anticipated that etanercept may also improve the long-term outcome of patients with rheumatoid arthritis and reduce the substantial economic burden imposed by the disease; however, more long-term data are needed to establish this.
