A systematic review of the effectiveness of adalimumab

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8 Background medication costs, especially in those treated with biological agents such as TNF inhibitors, account for a majority of the direct costs of RA. 57 Some drug intervention studies have shown reduced work absence with aggressive treatment strategies, 58 although only one-third of employed patients cease because of disease and, unsurprisingly, manual workers are much more likely to stop work. 59 Current service provision Most patients with RA are referred to hospital services for assessment, but up to one-quarter of those with early inflammatory arthritis (not necessarily RA) are managed in primary care. Most district general hospitals now have a department of rheumatology with varied support from clinical nurse specialists and other professionals allied to medicine. The majority of patients followed up in a hospital rheumatology department have RA or another type of inflammatory arthritis or connective-tissue disease. A proportion of such patients may also require inpatient treatment, although there are considerable variations in inpatient facilities and hospitalisation rates for RA. The Arthritis and Musculoskeletal Alliance (ARMA) has recently proposed standards of care for patients with inflammatory arthritis. The principal motive for these standards 60 is to improve service provision and delivery and to reduce regional variations in access to services. 61–63 For example, access to TNF inhibitors varies depending on local funding arrangements, such that some districts operate waiting lists for patients to begin treatment despite wide drug availability. A recent survey, commissioned by ARMA and the British Society for Rheumatology (BSR), with support from Schering-Plough, indicated that around one-third of 148 rheumatologists, mainly from England and Wales, were unable to prescribe TNF inhibitors. 64 Principal barriers to prescribing were identified as difficulties with local funding arrangements or problems of infrastructure such as the availability of day-case facilities or nursing support. Variable implementation of guidance on the use of TNF inhibitors was also confirmed by a survey of 196 hospitals and PCTs undertaken by the Audit Commission, which found that ‘the biggest perceived barrier to implementation among NHS bodies, for both clinical guidelines and technology appraisals, was lack of money. We found that 85 per cent of respondents identified that the funds available to implement technology appraisals were insufficient, particularly in relation to high-cost appraisals, such as … etanercept and infliximab for rheumatoid arthritis.’ 60 Access to adalimumab has caused particular difficulties in some areas because this drug has not yet been evaluated by NICE. However, some services have managed to secure additional funding for drugs and junior medical and nursing staff to enable NICE guidance to be implemented. 65 Description of the technology Adalimumab (Humira ® ; Abbott Laboratories) Adalimumab is a recombinant monoclonal antibody, made from human peptide sequences, which binds specifically to TNF and neutralises its biological functions by blocking interactions with the p55 and p75 cell-surface TNF receptors. Treatment is currently recommended for use in people with moderate or severe RA who have not responded to one or more DMARDs, including methotrexate. An application to extend the licence of adalimumab for use in severe, active, progressive RA in adults not previously treated with methotrexate was submitted by Abbott Laboratories in December 2004 66 and approved in June 2005. 67 Concomitant treatment with methotrexate is recommended for optimum efficacy, but adalimumab may be used alone where methotrexate is not tolerated or is contraindicated. Clearance of adalimumab from the body is decreased with age and by concomitant methotrexate administration, whereas adalimumab increases methotrexate clearance. 68 Patients normally self-administer adalimumab by subcutaneous injections, after training, at a standard dose of 40 mg every other week; but the dose may be increased to 40 mg weekly if disease is poorly controlled. 69 Etanercept (Enbrel ® ; Wyeth Laboratories) Etanercept is a combination protein consisting of the extracellular portion of two of the 75-kDa TNF receptors (TNF-R2) for TNF combined with a human Fc portion of human IgG class 1 (IgG 1). Etanercept binds soluble and cell-bound TNF- with high affinity and does this by competing with TNF receptors. Etanercept is administered as a twice-weekly subcutaneous injection of 25 mg or a once-weekly injection of 50 mg. Patients or caregivers normally administer etanercept, after suitable training. No dose changes are necessary for patients with renal or hepatic failure or in elderly subjects. Etanercept may be used in
combination with methotrexate or alone for the treatment of active RA in adults when the response to DMARDs, including methotrexate (unless contraindicated), has been inadequate, and for the treatment of severe, active and progressive RA not previously treated with methotrexate. Etanercept is also licensed for use in juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis and severe psoriasis. Infliximab (Remicade ® ; Schering-Plough) Infliximab is a recombinant chimeric human–murine monoclonal antibody that binds soluble and membrane-bound TNF-. Stable complexes are formed, binding of TNF- is prevented and TNF- already bound to TNF receptors may be dissociated. The TNF- binding region is of mouse origin and comprises 30% of the amino acid sequence of infliximab. The remainder is a human IgG 1 heavy-chain and kappa-chain constant region. Infliximab is licensed for use in RA with methotrexate, although in clinical practice it is used without methotrexate or with other DMARDs if patients are intolerant of methotrexate. 70 The recommended dose of infliximab for RA is 3mgkg –1 body weight given as an intravenous infusion, followed by further infusion, at the same dose, 2 and 6 weeks later. Thereafter, infusions are given at 8-week intervals. An interval between infusions of greater than 16 weeks is not recommended because of an increased risk of hypersensitivity reactions, although infusions after longer gaps have been administered safely. 62,71,72 Freshly reconstituted infliximab is diluted to a volume of 250 ml using 0.9% sodium chloride and the infusion is administered intravenously over at least 2 hours using a low-protein-binding filter. Treated patients should be observed for 1–2 hours post infusion. Recent studies indicate that patients who tolerate infusions well and are established on therapy may receive infusions over 1 hour or less. 73 Infliximab is also licensed for use in severe Crohn’s disease (5 mg kg –1 ), including disease complicated by fistulae, ankylosing spondylitis (5 mg kg –1 ) and psoriatic arthritis (5 mg kg –1 ). Use of higher doses of infliximab in trials has encouraged use of higher doses or a shorter interval between infusions in RA. 74 Special precautions for use of TNF inhibitors TNF inhibitors may cause a variety of adverse effects. 1 Reactivation of Mycobacterium tuberculosis organisms lying dormant in walled granuloma, in © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 42 individuals previously infected with tuberculosis, is a particular concern. Such ‘latent’ tuberculosis, thought to be highly prevalent in the world’s population, rarely causes disease. TNF- is a key component of host defence against M. tuberculosis, especially in the formation of granulomas. 75 Inhibition of TNF- appears to increase the risk of M. tuberculosis and other agents causing granulomatous diseases, such as Listeria monocytogenes (a bacterium associated with foodborne diseases) and Histoplasma capsulatum (a fungus which, in endemic areas, causes lung disease in people with a compromised immune system). The risk appears to be significantly greater with infliximab (53 patients per 100,000 treated cases) than with etanercept (28 per 100,000). 76 Data for adalimumab are limited, but an increased risk has also been shown. The summary of product characteristics (SPC) for adalimumab and infliximab and guidance including proposed guidance from the BSR, British Thoracic Society and the British Society for Gastroenterology recommend screening patients before treatment. 77 In RA this is currently done by taking a personal and family history of tuberculosis and a pretreatment chest X-ray, but the addition of skin tests using tuberculin has been proposed. Skin testing before the use of TNF inhibitors poses problems in the UK because of the use of bacille Calmette-Guérin (BCG) vaccination for tuberculosis prevention in childhood. In addition, many patients with RA are poorly responsive to tuberculin, perhaps as a result of previous or current immunosuppressive therapy, but also due to the disease. 78 Preventive antituberculous drug treatment in latent tuberculosis is also associated with a risk of druginduced hepatitis, which needs to be considered in deciding about prophylactic therapy. Routine blood monitoring is not necessary for patients taking TNF inhibitors, but may be needed for concomitantly used DMARDs such as methotrexate. TNF inhibitors can induce antinuclear and anti-double-stranded DNA antibodies in the blood of some patients treated with TNF inhibitors. These antibodies are associated with systemic lupus erythematosus (SLE), a potentially serious rheumatic disease. Cases of drug-induced SLE have been reported with TNF inhibitors, but are rare. 79 Choosing between TNF inhibitors and patient preferences Physicians may prefer one TNF inhibitor to another for clinical reasons; for example, etanercept or adalimumab may be preferred to 9
Page 1 and 2: A systematic review of the effectiv
Page 3 and 4: A systematic review of the effectiv
Page 5 and 6: Objectives: This report reviews the
Page 7: Glossary and list of abbreviations
Page 10 and 11: viii Glossary and list of abbreviat
Page 13 and 14: Background Rheumatoid arthritis (RA
Page 15: increased risk of serious infection
Page 19 and 20: Summary RA is a common, chronic, in
Page 21 and 22: (IL-2) and interleukin-6 (IL-6), pr
Page 23: Assessment of response to DMARDs Re
Page 27: disease between clinic appointments
Page 30 and 31: 14 Effectiveness in juvenile arthri
Page 32 and 33: 16 Effectiveness adalimumab plus me
Page 34 and 35: 18 Effectiveness Monoclonal Antibod
Page 36 and 37: 20 TABLE 1 Description of included
Page 38 and 39: 22 TABLE 2 Quality of included RCTs
Page 40 and 41: 24 Effectiveness change in modified
Page 42 and 43: 26 Effectiveness TABLE 4 Meta-analy
Page 44 and 45: 28 Effectiveness Review: Adalimumab
Page 46 and 47: 30 Effectiveness Review: Adalimumab
Page 48 and 49: 32 TABLE 6 Effectiveness Descriptio
Page 50 and 51: 34 TABLE 6 Effectiveness Descriptio
Page 52 and 53: 36 TABLE 7 Effectiveness Quality of
Page 54 and 55: 38 Effectiveness etanercept trials.
Page 56 and 57: 40 Effectiveness TABLE 9 Summary of
Page 58 and 59: 42 Effectiveness Review: Etanercept
Page 70 and 71: 54 Effectiveness TABLE 11 Summary o
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58 TABLE 13 Quality of included RCT
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60 Effectiveness per week and escal
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62 Effectiveness significant advant
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64 Effectiveness Review: Infliximab
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66 Effectiveness Review: Infliximab
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68 Effectiveness FIGURE 44 Malignan
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70 TABLE 17 Effectiveness Summary o
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Summary of review of existing econo
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TABLE 20 Summary of published ICERs
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TABLE 21 Published etanercept econo
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TABLE 23 Published economic analyse
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TABLE 25 Treatment sequences: adali
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management of RA, i.e. 1st and 2nd
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To estimate the long-term consequen
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TABLE 32 TNF inhibitors as last act
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TABLE 34 Basic structure of the mod
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een quit on grounds of toxicity, ad
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TABLE 39 Strategy set: adalimumab a
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TABLE 43 Beta distributions for HAQ
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TABLE 44 Early cessation of DMARDs:
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TABLE 46 Unit costs for tests and v
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following properties, according to
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TABLE 52 Base case: TNF inhibitors
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TABLE 54 Base case: TNF inhibitors
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TABLE 59 Third TNF inhibitor follow
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TABLE 65 Sensitivity analyses: TNF
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TABLE 67 Sensitivity analyses: TNF
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The substantial economic impact of
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Summary Effectiveness: principal fi
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inhibitors, although the incrementa
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introduce bias which generally exag
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Adalimumab, etanercept and inflixim
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1. Jobanputra P, Barton P, Bryan S,
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46. Young A, Dixey J, Cox N, Davies
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tumor necrosis factor therapy in th
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arthritis: a 12-week, double-blind,
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171. Geborek P, Crnkic M, Petersson
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216. Schotte H, Willeke P, Mickholz
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The Health Assessment Questionnaire
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Cochrane Library (CENTRAL) 2005 Iss
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Appendix 3 © Queen’s Printer and
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TABLE 69 Studies excluded from clin
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148 Appendix 4 TABLE 71 Meta-analys
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150 Appendix 4 TABLE 73 Meta-analys
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152 Appendix 4 Infliximab versus pl
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154 Appendix 4 Infliximab plus MTX
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Ovid MEDLINE(R) 1966 to February we
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Appendix 8 © Queen’s Printer and
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TABLE 79 Wong et al., 2002 161 © Q
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TABLE 80 Kobelt et al., 2003 162 (c
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TABLE 82 Brennan et al., 2004 160
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TABLE 85 Bansback et al., 2005 166
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176 Appendix 9 TABLE 89 Strategy se
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Extensive sensitivity analysis was
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TABLE 96 Variation 1: TNF inhibitor
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TABLE 99 Variation 2: TNF inhibitor
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TABLE 102 Variation 3: TNF inhibito
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TABLE 132 Variation 10: TNF inhibit
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A systematic review of the effectiveness of adalimumab

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