GUIDELINES FOR PRESCRIBING TNF-α BLOCKERS IN ADULTS WITH RHEUMATOID ARTHRITIS. Report of a Working Party of the British Society for Rheumatology - PDF

GUIDELINES FOR PRESCRIBING TNF-α BLOCKERS IN ADULTS WITH RHEUMATOID ARTHRITIS y The news of treatment advances is always exciting for people with arthritis and those treating them. Any new treatment will

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GUIDELINES FOR PRESCRIBING TNF-α BLOCKERS IN ADULTS WITH RHEUMATOID ARTHRITIS y The news of treatment advances is always exciting for people with arthritis and those treating them. Any new treatment will have undergone a long development process including small-scale volunteer trials on normal subjects and then limited clinical trials. If a new drug passes these hurdles and is shown to be efficacious and safe in the short term, it may be granted a product licence for general use. Its acceptance as part of the range of treatment options used to treat people with arthritis will then depend on whether wider use proves its effectiveness and on whether, in the long term, efficacy outweighs risk. This report relates to a new class of therapy, the tumour necrosis factor (TNF-α) blockers. Trials have shown these to be effective in rheumatoid arthritis and two drugs of this class were licensed for treatment of rheumatoid arthritis in Further guidelines may be required over time to assist with the introduction of other new treatments. Background Rheumatoid arthritis affects some half a million people in the UK causing persistent pain and disability. The secondary care costs for the first five years of disease have been estimated at 22 million 1 with the majority of costs generated by a small proportion of patients with severe disease. Costs rise substantially in late disease due to the need for operations and institutional care with a total annual cost to society of over one billion pounds 2 3. Tumour necrosis factor (TNF-α) blockers have the potential to produce radical relief of patients symptoms and improve their prognosis. Potential long-term benefits could include: reduced need for joint replacement surgery reduced demands on physiotherapy, occupational therapy and podiatry reduced demands on medical and nursing services reduced needs for other medicines reduced demands on social services and carers improved quality of life increased prospect of remaining in work increased life expectancy As a result, significant savings in medical, social services and welfare benefits budgets could be achieved, although, at the same time, the treatments will involve significantly higher demands on the drugs budget. Ideally, these treatments should be available to all patients who might benefit from them. One of the two available drugs, infliximab, was launched for use in Crohn s disease, an inflammatory disorder of the intestine, in September The development of these new therapies presents all those concerned with the welfare of people with arthritis with some significant challenges. In the short term, because of their cost, there is a danger that people s access to the new treatments will be determined more by where they happen to live than by clinical need - so called postcode prescribing. To avoid this, there is a need for national guidelines to provide guidance to clinicians and health planners as to when to prescribe the new therapies on clinical grounds and to explain to people with arthritis in a clear and accessible way the basis on which these decisions are being made. In the medium term, if the treatments prove their worth in general use, there will be a need to argue for a further increase in expenditure. Careful monitoring of the medical, social and economic impact of the new treatments will be an essential part of this approach, in other words what the Government calls joined up thinking. The National Institute of Clinical Excellence (NICE) is undertaking an assessment of these new treatments in Further evidence from trials in progress must also be monitored. National Guidelines The following guidelines are recommended to ensure that the new treatments are introduced in as systematic and planned a way as possible to ensure the greatest possible benefit to people with arthritis. They have been developed by a Working Party set up by the British Society for Rheumatology with representation from patients (Arthritis Care), research (the Arthritis Research Campaign), public health and general practice and have been drawn up on the basis of published trial data. A graded list of the scientific papers we have examined is appended, along with a list of members of the Working Party. Any potential conflict of interest in the Party drawing up the guidelines has been stated. The guidelines have been developed for use by prescribing clinicians and for consideration by commissioners of secondary care rheumatology services. They are intended to indicate which patients may benefit from the new therapies. It is important to stress that clinical recommendations for use can only be based on the clinical evidence available. As current trials have been carried out in circumscribed study populations, these guidelines necessarily involve restricting access to these new treatments in the short term. However, the new therapies are not necessarily the only available treatment option for patients who do satisfy these guidelines. The risks and potential risks, as well as the benefits must be considered. There will be circumstances in which the rheumatologist feels that there is another lower cost drug(s) which is equally likely to produce a good clinical response in the individual patient, in which case this should be discussed with the patient. Registry The situation with respect to the availability and use of biologic agents will evolve. It is meanwhile necessary to establish a review system that will monitor use, benefit and side effects; there are various models for organisation and sponsorship but there are compelling arguments for developing a specialty-run register. 2 The BSR & EULAR are supporting the establishment of a Registry of all patients who are treated with the new biologic agents. An appropriate control group of untreated patients will also be recruited. The aim of this Registry is to study the short-term and long-term toxicity of these agents - in particular the incidence of serious infections, the development of malignancy, and mortality. For the first three years after initial treatment patients should be followed using patient completed diaries and via their hospital records for the development of serious infections. Monitoring for malignancy and mortality will be continued for at least five years via the NHS Central Registry. Rheumatologists will be contacted on a six-monthly basis for details of the total dose and mode of administration of the new therapies. Approval for the establishment of this Registry has been obtained from the NorthWest Multi-Centre Research Ethics Committee (MREC). Informed consent will be sought from patients for their participation in this follow-up study. The guidelines recommend careful clinical monitoring of patients. For this reason it is recommended that the new treatments will only be prescribed in the secondary care sector at this stage. These guidelines will be reviewed and revised by the BSR as new evidence becomes available and will be posted on the BSR website. 3 British Society for Rheumatology Working Party on New Treatments Working Party Membership Dr Andrew Bamji (CHAIR) (Consultant Rheumatologist, Queen Mary s Hospital, Sidcup; Chairman, Clinical Affairs Committee, British Society for Rheumatology) Ms Jean Bradlow (Assistant Director of Public Health, Oxfordshire Health Authority) Dr Robin Butler (Consultant Rheumatologist, Robert Jones & Agnes Hunt Hospital, Oswestry; Honorary Secretary, British Society for Rheumatology) Dr David Doyle (Consultant Rheumatologist, Whipps Cross Hospital, London; Secretary, Joint Specialty for Rheumatology Committee of the Royal College of Physicians and British Society for Rheumatology; Honorary Officer, British League Against Rheumatism; Trustee & Chairman, Arthritis Care Medical Advisory Committee) Ms Sophie Edwards (External Relations Manager, British Society for Rheumatology; Chief Executive, British League Against Rheumatism) Dr Jane Griffin (Consultant Rheumatologist, Chase Farm Hospital, Enfield; Clinical Affairs Committee, British Society for Rheumatology; Arthritis Care Medical Advisory Committee) Mr Richard Gutch (Chief Executive, Arthritis Care) Dr Brian Hazleman (Consultant Rheumatologist, Addenbrookes Hospital, Cambridge; President, British Society for Rheumatology) Dr Gill Hosie (President, Primary Care Rheumatology Society) Mr Fergus Logan (Chief Executive, Arthritis Research Campaign) Dr Tom Palferman (Consultant Rheumatologist, Yeovil District General Hospital, Yeovil; Vice- Chairman, Clinical Affairs Committee, British Society for Rheumatology) Dr Duncan Porter (Consultant Rheumatologist, Gartnavel General Hospital, Glasgow) Dr David Rampton (Consultant Gastroenterologist, Barts & the London NHS Trust, London; Reader in Gastroenterology, Barts & the Royal London School of Medicine and Dentistry, London; British Society of Gastroenterology) Professor Deborah Symmons (Consultant Rheumatologist, East Cheshire NHS Trust; Professor of Rheumatology and Musculoskeletal Epidemiology, ARC Epidemiology Unit, Manchester) References 1. Cooper NJ, Mugford M, Scott DGI, Barrett EM, Symmons DPM. Secondary health service care and second line drug costs of early inflammatory polyarthritis in Norfolk, UK. J Rheumatol 2000, 27: Pugner KM, Scott DL, Holmes JW, Hieke K. The costs of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum 2000, 29: McIntosh E. The cost of rheumatoid arthritis. Br J Rheumatol 1996, 35: GUIDELINES FOR PRESCRIBING TNF-α BLOCKERS IN ADULTS WITH RA Introduction Prevalence and incidence of Rheumatoid Arthritis Rheumatoid Arthritis (RA) is the commonest inflammatory polyarthropathy in the UK, with an annual incidence of new cases of approximately 54/100,000/year for women and 25/100,000 for men i. It is a chronic disorder, with a course that often exceeds 20 years, and a prevalence of established disease of approximately /100,000 ii. In a Health Authority area with a population of 500,000 adults, approximately 250 new cases each year, and 3000 prevalent cases, may be expected. Clinical impact of disease RA varies in its clinical manifestations and severity, but in many cases, it is a progressive, destructive and disabling condition. In an inception cohort of newly diagnosed RA patients, 44% of patients became unable to work, as a result of their RA, over the ensuing 10 years iii. With increasing age and disease duration, an increasing proportion of patients require major joint surgery, such that after 20 years of disease, approximately 25% of RA patients will have undergone joint replacement surgery. iv Patients with RA have increased mortality rates; this is most marked in patients attending specialist rheumatology clinics, increasing with disease severity and disease duration v. In the most severely affected RA patients, mortality is increased to a degree that is comparable to that seen in triple vessel coronary artery disease vi. Economic impact of RA In 1992, the total economic impact of RA in England was estimated to be 1.3 billion vii, of which approximately half was due to indirect costs of loss of production. The direct costs were attributed to hospitalisation, outpatient care, drugs, residential care and social services provision, with hospitalisation consuming the largest proportion of expenditure. The costs associated with RA rise steeply with disease severity when compared to patients with mild disease, patients with severe RA consume 20 times more resources. viii Therapy that substantially reduces long term disease progression could be expected to reap cost savings in the long term for example, by reducing the number of joint replacements required - which should be offset against the short term costs associated with therapy. Therapy for RA Modern management of RA revolves around the early diagnosis, and early use of disease modifying anti-rheumatic drugs (DMARDs) in an attempt to suppress joint inflammation, thereby limiting the amount of joint damage that accrues over the long course of the disease. Newly diagnosed RA patients are usually treated with either sulphasalazine or methotrexate, which are of equal efficacy in early RA. ix Patients with a poor response to initial therapy are changed to an alternative DMARD, or are commenced on combination DMARD therapy, but a proportion of patients respond sub-optimally to all currently available DMARDs, whether used singly or in combination. 5 TNF-α blockers There are two compounds licensed for use in the treatment of active RA in the UK and USA. Etanercept (Enbrel, Wyeth) is a recombinant human TNF receptor:fc fusion protein consisting of a dimer of the extracellular portion of two p75 receptors fused to the Fc portion of human IgG1. It is administered subcutaneously at a dose of 25mg twice weekly. Infliximab (Remicade, Schering-Plough) is a chimeric human-murine monoclonal antibody administered by slow intravenous infusion at weeks 0, 2, 6 and 8 weekly thereafter at a dose of 3mg/kg, and is used in combination with oral methotrexate. Clinical efficacy - monotherapy In Europe, the disease activity score (DAS 28) is a validated instrument which is often used to assess disease severity and response to treatment x. Response to therapy in RA is also often described using American College of Rheumatology definitions of ACR 20 (20% improvement in a selection of measures of disease activity), ACR 50 (50% improvement) and ACR 70 (70% improvement) response. Response rates are influenced by the study population. ACR response rates to sulphasalazine, methotrexate, leflunomide, infliximab and etanercept are shown below: Examples of Double blind Randomised Controlled Trials of anti-tnf monotherapy comparison with sulphasalazine, methotrexate (MTX) and leflunomide Drug No of patients Disease duration Assessment period ACR 20 response ACR 50 response ACR 70 response Etanercept yrs 6 months 59% 40% 15% 25mg xi Etanercept yrs 12 months 60%** 33%** 16%** 10mg xx Etanercept yrs 12 months 72% 48%** 26%** 25mg xx Infliximab yrs 4 months 55%* 42%* 3mg/kg xii Infliximab 10mg/kg xii yrs 4 months 60%* 36%* SASP yrs 6 months 56% 30% 2g/day xiii Leflunomide xiv yrs 12 months 52% 34% 20% MTX yrs 12 months 65% 42%** 21%** 20mg/wk xx MTX mg/wk xiv yrs 12 months 46% 23% 9% * Paulus response ** estimated from figure 6 In a randomised-controlled trial, which compared etanercept with methotrexate in patients with RA of less that 3 years duration who had not previously received methotrexate, etanercept acted significantly more rapidly to decrease symptoms and signs of active RA. However the proportions of patients achieving ACR 20, 50 or 70 responses at 12 months did not differ significantly between the groups. Although both etanercept and infliximab appear to be more effective than standard therapy, their use cannot be justified in patients who might respond equally well to much cheaper conventional therapy with sulphasalazine or methotrexate with which there is extensive long-term clinical experience. Clinical efficacy combination therapy Most interest has focussed on patients who have proved themselves to be resistant to standard DMARD therapy. These are the patients with the most severe disease, with high morbidity and mortality, associated with high cost of care. Trials that have studied the benefits of adding TNFα blockers to patients with continuing disease activity despite adequate therapy with methotrexate are shown below: Examples of Double blind Randomised Controlled Trials of addition of TNF-α Blockers to patients with inadequate response to MTX comparison with cyclosporin Drug added No of patients Disease duration Assessment ACR 20 response ACR 50 response ACR 70 response Etanercept 25mg xv yrs 6 months 71% 39% 15% Infliximab 3mg/kg / yrs 6 months 53%* 29% 11% wk xvi Infliximab 3mg/kg/ yrs 6 months 50%* 27% 8% wk xvi Infliximab 10mg/kg/ yrs 6 months 58%* 26% 11% wk xvi Infliximab 10mg/kg/ yrs 6 months 52%* 31% 18% wk xvi Infliximab 3mg/kg/4 86 9yrs 54 weeks 48% 34% 17% wk xxi Infliximab 3mg/kg/ yrs 54 weeks 42% 21% 10% wk xxi Infliximab 10mg/kg/ yrs 54 weeks 59% 38% 19% wk xxi Infliximab 10mg/kg/8 wk xxi 87 11yrs 54 weeks 59% 39% 25% Cyclosporin 2.5-5mg/kg/day xvii yrs 6 months 48% * approximate ACR response rate (read from figure) 7 It has proved difficult to reproduce the results obtained with cyclosporin, because of drug toxicity. Methotrexate and TNF-α blockers are synergistic and the data show that combining the two agents in methotrexate-resistant patients results in a substantial response rate. Quality of life Infliximab (3mg/kg every four weeks or 10mg/kg every four or eight weeks) plus methotrexate had a significantly greater effect on arthritis-specific function as assessed by the HAQ than did methotrexate alone xxi. The combination also had significantly greater beneficial effect on scores for the physical component of the SF-36 General Health Survey questionnaire than methotrexate alone, and for the vitality and social-functioning subscales of the mental component of the SF- 36 xxi. Radiological outcome There is now evidence that both etanercept and infliximab will improve radiological outcome. The mean increase in erosion score at 12 months was 0.47 for etanercept compared with 1.03 for methotrexate (p= 0.002) xx. There was no deterioration in erosion score in 72% of etanercepttreated patients compared with 60% of those given methotrexate. The rates of joint space narrowing were low and prevented by both drugs. Patients who had the best clinical responses had the smallest amount of radiological progression. There was a 9-10% deterioration in total radiographic score in patients given methotrexate alone over 54 weeks whereas there was no significant change in groups who received infliximab as well as methotrexate xxi. The rate of progression of joint damage was reduced in those patients on infliximab who failed to show a clinical response as well as in those who did. Toxicity In post-marketing use in the USA, serious infections and sepsis, including some fatalities, have been reported. Many of these events occurred in patients predisposed to infections, such as those with advanced or poorly controlled diabetes. There have been a few reports of tuberculosis in patients treated with infliximab, and of blood dyscrasias and demyelination with etanercept. Injection site reactions are common with etanercept and infusion-related events including headache, diarrhoea, rash, fever, chills, urticaria and dyspnoea have been reported with infliximab. There is a theoretical risk of immunosuppression and malignancy as a result of the mode of action of TNF-α blockers but there are as yet no long term studies to quantify these risks. Effects on pregnancy are unknown. Eligibility for treatment with biologic therapies All patients must satisfy the 1987 criteria of the American College of Rheumatology Classification criteria for a diagnosis of Rheumatoid Arthritis xviii. 8 1. Active RA The method used to assess disease activity must be strictly defined, objective and robust. Candidate measures include: Composite disease activity score (DAS) based on 28 joint swelling count, 28 joint tenderness count, ESR and patient global assessment of disease activity. This score is used in the EULAR definition of good response and remission. Good response to therapy includes two components (1) improvement relative to the past (a fall in DAS by 1.2) and (2) improvement to a level of low activity (DAS 3.2). A score of 5.1 indicates a high activity of disease. Multiple measures of disease activity e.g. ACR core measures of disease activity. This assesses response to treatment in comparison with baseline, but has the disadvantage that it does not give an overall score which could be used as an entry criterion for treatment. The definition of improvement (ACR 20% or 50% improvement) does not include a component relating to the achievement of low disease activity. Measurements of disease
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