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Malottki K, Barton P, Tsourapas A, et al. Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Mar. (Health Technology Assessment, No. 15.14.)

1Background

Summary

Rheumatoid arthritis (RA) is a common inflammatory condition that typically causes a symmetrical chronic arthritis that causes joint pain, swelling and in some cases a systemic illness. The cause of RA is unknown, but important genetic influences are recognised. The goal of treatment is to achieve remission if patients present with early disease. In later disease, key goals are to control pain and inflammation and thereby reduce functional limitations and the risk of permanent joint damage.

Timely use of disease-modifying antirheumatic drugs (DMARDs) is an essential aspect of contemporary disease management, but many patients may not respond even when conventional agents are used optimally. DMARDs are defined by their ability to modify the disease process such that the risk of progressive joint damage is reduced. Biological agents designed to interrupt the inflammatory pathway have proved to be an important advance in the care of RA patients. The most widely used agents in the UK are tumour necrosis factor inhibitors [adalimumab (ADA), etanercept (ETN) and infliximab (IFX)], and a monoclonal antibody targeting B lymphocytes [rituximab (RTX)]. The use of these agents is subject to National Institute for Health and Clinical Excellence (NICE) guidance, and all are approved for use provided specific criteria are met. Other agents such as anakinra (an interleukin-1 inhibitor), abatacept (ABT, an antibody that targets cellular interactions) and tocilizumab (an interleukin-6 inhibitor) are licensed but currently are not approved for use by NICE.

This review considers the clinical effectiveness and cost-effectiveness of ADA, ETN, IFX, RTX and ABT when used in patients with RA who have tried conventional agents including methotrexate and have failed to improve after trying a first tumour necrosis factor inhibitor.

Description of underlying health problem

Clinical features of rheumatoid arthritis

Rheumatoid arthritis (RA) typically begins in middle age and more affects more women than men. Pathologically the disease is characterised by an inflammatory reaction and increased cellularity of the lining layer of synovial joints. Joints such as the proximal interphalangeal joints, metacarpophalangeal joints, wrists, elbows, cervical spinal joints, knees, ankle and foot joints are commonly affected. Affected joints become stiff after periods of inactivity, for example in the morning, become swollen and are variably painful. Other organ systems may also be affected. Patients commonly experience fatigue and blood abnormalities such as anaemia and a raised platelet count. Weight loss, lymph node enlargement, lung diseases (such as pleurisy, pleural fluid and alveolitis), pericarditis, vascular inflammation (vasculitis), skin nodules and eye diseases (reduced tear production or inflammation) may also occur.

The severity of disease, its clinical course and individual responses to treatment vary greatly. Symptoms of RA may develop within days or evolve over many weeks and months.1 Several distinct patterns of joint disease are recognised, including predominantly small or medium joint disease; predominantly large joint disease; flitting or transient attacks of joint pain (palindromic rheumatism); pain and stiffness of the shoulder and pelvic girdles (polymyalgic disease); disease associated with weight loss and fever (systemic onset); or any combination of these. Pain and disability in early RA is linked to disease severity and to measures of psychological distress.2 Disease progression can be relentless or punctuated by partial or complete remissions of variable and unpredictable intervals.

Diagnosis of rheumatoid arthritis

Rheumatoid arthritis is diagnosed from a constellation of clinical, laboratory and radiographic abnormalities. Diagnosis may be obvious or may need specialist assessment or a period of clinical observation. Internationally agreed classification criteria for RA are used widely in contemporary research studies,3 but it is widely acknowledged that current criteria need to be revised. Current criteria include morning stiffness in joints exceeding 1 hour, physician-observed arthritis of three or more areas, arthritis involving hand joints, symmetrical arthritis, rheumatoid skin nodules, a positive blood test for rheumatoid factor (RF) and radiographic changes typical of rheumatoid disease. Such criteria have limited utility in routine practice and most clinicians diagnose RA without reference to them, as many patients do not meet formal disease classification criteria early in their disease.4

Epidemiology

Rheumatoid arthritis affects around 0.5%–1% of the population, three times as many women as men and at age of onset peaks between the ages of 40 years and 70 years. Prevalence of disease at 65 years of age is six times that at 25 years of age. Recent estimates from England and Wales show an annual incidence of 31 per 100,000 women and 13 per 100,000 men, suggesting a decline in recent decades, and a prevalence of 1.2% in women and 0.4% in men.5 The National Audit Office (NAO) estimates that around 580,000 people have RA in England and that 26,000 patients are diagnosed each year.6

Aetiology

A specific cause for RA has not been identified. There appear to be many contributing factors including genetic and environmental influences. Genetic influence is estimated at 50%–60%.7 The risk of RA in both members of a pair of monozygotic twins is 12%–15% and a family history of RA gives an individual a risk ratio of 1.6 compared with the expected population rate.8 Many of the genes associated with susceptibility to RA are concerned with immune regulation. For example, the human leucocyte antigen HLA-DRB1, which contributes the greatest risk, and PTPN22, which makes the second most important genetic contribution in Caucasian populations, are both involved in T-lymphocyte activation and signalling.9,10

Infectious agents have been suspected but no consistent relationship with an infective agent has been shown. Sex hormones have also been suspected because of the higher prevalence of RA in women and a tendency for disease to improve in pregnancy. However, a precise relationship has not been identified. A causal link with lifestyle factors such as diet, occupation or smoking has not been shown.

Pathology

Synovial joints occur where the ends of two bones, covered with hyaline cartilage, meet in a region where free movement is desirable. This joint space is encapsulated by a fibrous capsule lined on the inside by a synovial membrane, which functions to secrete fluid to lubricate and nourish hyaline cartilage. In RA the synovial layer of affected joints becomes enlarged as a result of increased cellularity or hyperplasia, infiltration by white blood cells and formation of new blood vessels. This is accompanied by increased fluid in the joint cavity, which contains white blood cells and a high level of protein (an exudate), contributing to the joint swelling. Bony erosions of cartilage and bone occur where synovial tissue meets cartilage and bone. This occurs through the combined actions of synovial tissue (pannus) and resident cartilage and bone cells. Erosions and loss of cartilage are rarely reversible. Such damage, therefore, compromises the structure and function of a normal joint.

Pathogenesis and biological targets in rheumatoid arthritis

A detailed discussion of the pathogenesis of RA is beyond the scope of this report. This subject is reviewed comprehensively elsewhere.1113 The synovial membrane in RA contains activated immune cells such as B and T lymphocytes and macrophages. These cells accumulate in synovial tissue. Cells resident in normal joints including synovial fibroblasts, cartilage cells (chondrocytes) and bone cells (osteoclasts) are also activated. Different cytokines, or small proteins, are produced by particular resident and infiltrating cells and aid intercellular communication and influence cellular and tissue behaviour.

A number of cytokines involved in this inflammatory cascade are seen as potential targets for intervention in RA. Drugs that target cytokines and which are licensed or are at a late stage of development currently include anakinra (directed against interleukin-1), tocilizumab [(TOC, RoActemra®, Roche) targeting interleukin-6] and tumour necrosis factor (TNF) inhibitors [including adalimumab (ADA, Humira®, Abbott Laboratories), certolizumab (Cimzia®, UCB), etanercept (ETN, Enbrel®, Wyeth Pharmaceuticals), golimumab (Simponi®, Schering-Plough Ltd) and infliximab (IFX, Remicade®, Schering-Plough Ltd)]. Other agents include abatacept [(ABT, Orencia®, Bristol-Myers Squibb Ltd) also known as CTLA4Ig], which interferes with T-cell activation, and rituximab (RTX, Mabthera®, Roche), which depletes B lymphocytes. Many other potential targets have been identified and a number of novel agents are in clinical trials.14

Management of rheumatoid arthritis

The current management of RA is described in detail in a recent National Institute for Health and Clinical Excellence (NICE) guideline.15 An exhaustive review of management is not provided here. We focus on aspects of disease management that are relevant to the decision problem in this appraisal.

Non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics are commonly used for symptom relief in RA. These drugs do not modify the disease process and key recommendations in NICE guidance centre on minimising the use of NSAIDs because of the potential toxicity of these agents. Corticosteroids are used widely and in a variety of ways. High doses given orally or parenterally (by a variety of routes) are used for the short-term control of disease while waiting for the effects of disease-modifying antirheumatic drugs (DMARDs). Low-dose glucocorticoids are also commonly used either as sole therapy or in combination with DMARDs. Low-dose glucocorticoids have important disease-modifying effects in RA.16

Disease-modifying antirheumatic drugs may be divided into conventional DMARDs, which include azathioprine (AZA), ciclosporin A (CyA), gold [GST (given by intra-muscular injection)], hydroxychloroquine (HCQ), leflunomide (LEF), methotrexate (MTX) and sulfasalazine,1719 and newer targeted biological agents, described below. Conventional DMARDs such as penicillamine are now used rarely.18 Conventional DMARDs may be used in combination, especially where there is a poor response to a single DMARD. For example, in early disease MTX is commonly combined with sulfasalazine and HCQ. There are few direct comparisons of individual DMARDs in early disease, but MTX is regarded as the standard against which other drugs should be compared. Most conventional DMARDs have specific dosing and monitoring schedules that require regular visits to a health-care facility and blood tests. How this is managed varies greatly in the UK; for example, in some centres all patients are seen in hospital clinics for drug monitoring whereas in others this occurs largely in the community.

The key objective in early RA management is to achieve remission. Many patients with early inflammatory arthritis (which often does not meet international classification criteria for RA) are able to achieve remission and treatment may be withdrawn in a proportion without relapse.20 This occurs in randomised trials or therapeutic studies with conventional DMARDs2124 used as monotherapy or in combination, conventional DMARDs combined with TNF inhibitors and also in observational studies. While these reports focus on the excellent outcomes achieved, it is important to recall that 57% of patients with early RA treated with a protocol designed to minimise disease do not achieve remission, around one-third do not achieve their treatment goal and between 31% and 54% of patients have progressive joint damage depending on the treatment strategy after 4 years of treatment.25

The NICE RA guidance recommends the use of MTX combined with another DMARD and corticosteroids (used short term) for disease control in early, severe RA. Practice varies; however, and evidence for combining DMARDs is limited and controversial.2628 Not all rheumatologists accept the need for DMARD combinations. Some prefer to step up therapy by adding another DMARD to MTX if the disease is inadequately controlled and others choose to replace the first DMARD with a second drug.29 A necessity for long-term use of multiple medications plainly requires an open dialogue and shared decision making between patients and health professions,30 especially where expert opinion differs.

In England and Wales patients who have failed to respond to (or tolerate) at least two DMARDs, including MTX at optimal doses, are eligible for TNF inhibitors subject to NICE guidance. Patients who do not respond to TNF inhibitors may be treated with RTX, a monoclonal antibody that depletes B lymphocytes. Other biological therapies such as anakinra, ABT and TOC are not currently approved for use by NICE. The relevant NICE guidance concerned with biologic therapies is described briefly below (see Current service provision).

Controlling symptoms of joint pain and stiffness, minimising loss of function, improving quality of life (QoL) and reducing the risk of disability associated with joint damage and deformity are central objectives in the management of RA at all stages. These objectives are not met with drug therapy alone: patients often need advice and support from a multidisciplinary team including specialist nurses, podiatrists, physiotherapists and occupational therapists. Since RA is a heterogeneous disease, which may vary over time, a long-term plan with regular clinical evaluation to assess disease status, disease complications, comorbidity, patient preferences and psychosocial factors is essential and is aided by well-informed and satisfied patients and carers.31,32 Indeed a key element of a Scottish trial reporting excellent outcomes was frequent specialist review with a focus on tight disease control.21

With advanced joint damage surgical intervention such as joint replacement arthroplasty, joint fusion or osteotomy may be necessary. Long-term observations show that around a quarter of patients with RA undergo a total joint arthroplasty.33 It cannot, of course, be assumed that all such surgery is directly attributable to RA, especially as osteoarthritis is the most prevalent form of arthritis. Other surgical interventions such as removal of synovial tissues and rheumatoid nodules, peripheral nerve decompression (such as in carpal tunnel syndrome) or soft tissue procedures such as tendon release or repair may be necessary at any stage of disease.

Assessment of response to disease-modifying antirheumatic drugs and biologic therapies

ACR response criteria

Modern clinical trials rely on composite end points such as the American College of Rheumatology (ACR) definition of improvement and the Disease Activity Score (DAS). The ACR response requires an improvement in the counts of the number of tender and swollen joints (using designated joints) and at least three items from the following: observer evaluation of overall disease activity; patient evaluation of overall disease activity; patient evaluation of pain; a score of physical disability [such as the Health Assessment Questionnaire (HAQ); see below]; and improvements in blood acute phase responses [e.g. erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)].

Response is defined as ACR20, ACR50 or ACR70, where figures refer to the percentage improvement of these clinical measures. This creates a dichotomous outcome of responders and non-responders. Achieving an ACR20 response has been regarded as a low hurdle, but in clinical practice patients who achieve this hurdle often gain a worthwhile clinical response, especially in early RA. ACR response criteria are described in more detail in Appendix 1.

DAS response criteria

The DAS score is calculated using a formula that includes counts for tender and swollen joints, an evaluation by the patient of general health (on a scale of 0 to 100) and blood acute phase (usually a log of the ESR, but more recently using CRP). DAS response criteria are described in more detail in Appendix 1. Originally DAS was based on an assessment of 53 joints for tenderness and 44 joints for swelling. Disease Activity Score 28 (DAS28), based on an evaluation of 28 joints, is used widely in routine clinical practice, partly as a result of NICE guidance on use of TNF inhibitors. DAS28, like DAS, is a continuous scale with a theoretical range from 0 to 10. Thresholds have been suggested for the scale such that a score greater than 5.1 is regarded as indicating high disease activity, a score of less than 3.2 low disease activity and a score of less than 2.6 remission.34,35 Achieving a DAS28 score of less than or equal to 3.2 and improving the score by greater than 1.2 is regarded to be a good response while achieving a score of less than or equal to 3.2 and improving by greater than 0.6 but less than 1.2 is regarded as a moderate response. Current NICE guidance for TNF inhibitors demands that patients should improve DAS28 by 1.2 in order to justify continuing treatment. It has been suggested that NICE guidance should be altered to allow patients who have attained a moderate response to continue treatment with a TNF inhibitor.36

While DAS28 scores are a very valuable tool for assessing treatment responses in groups of patients, scores have important limitations when used for individual patient decisions. For example, DAS28 does not incorporate ankle and foot disease. Thus, a patient with disease localised here may not attain a sufficiently high score to be eligible for a TNF inhibitor. DAS28 also shows poor concordance with clinical judgement (based on a wide range of parameters).37 In addition, the degree of measurement error in a test–retest reliability study indicates that the faith placed in DAS28 as the sole decision-making tool is misplaced.38 For example, the smallest detectable difference which should be exceeded if a clinician is to be 95% confident that a change exceeds measurement variability was 1.32 for DAS28.

The Health Assessment Questionnaire

The HAQ is a family of questionnaires designed to assess functional capacity of patients.39 The most widely used version of HAQ is the modified HAQ (MHAQ) score which comprises eight items such as an ability to dress, get in and out of bed, lift a cup, walk outdoors and wash. MHAQ is reported as an average score across the eight categories such that 0 indicates an ability to achieve tasks without difficulty and 3 reflects an inability to achieve tasks. Scores therefore range between 0 and 3 with an interval of 0.125. Low scores indicate better function. Care is needed in the interpretation of HAQ scores in published studies because there are several modifications to HAQ. The HAQ score is described in more detail in Appendix 1.

Radiographic measures

Radiographic outcomes are believed by many to be the most important outcome measure in RA. However, variation in joint inflammation has a more profound and immediate impact on disability compared with the slow and cumulative effect of radiographic damage on disability.40

The most commonly used tools for assessing joint damage are the Sharp and Larsen methods and their modifications (see Appendix 1), which rely on evaluations of plain radiographs of hands and feet. Plain radiographs are rather insensitive to change but are cheap and widely available. A majority of patients show only mild or no progression on plain radiographs over periods of 1–2 years, highlighting one of their limitations in modern clinical trials.41

Prognosis

The impact of RA on an individual can be viewed from a variety of perspectives including employment status, economic costs to the individual or society, QoL, physical disability, life expectancy and medical complications such as extra-articular disease and joint deformity, radiographic damage or the need for surgery. In general, persistent disease activity is associated with poorer outcomes, although in the first 5 years of disease physical function is especially labile. Greater physical disability at presentation is associated with greater disability later in disease. Other factors linked with poorer function include older age at presentation, the presence of rheumatoid nodules, female sex, psychological distress and degree of joint tenderness.42 Continued employment is related to the type of work and other aspects of the workplace such as pace of work, physical environment, physical function, education and psychological status; work disability is not necessarily linked to measures of disease activity.43,44 Radiographic damage in RA joints is also influenced by RF status, age, disease duration and extent of disease and perhaps genetic factors.

Life expectancy in RA is reduced and is related to age, disability, disease severity, comorbidity and RF status, in particular.4548 For example, a 50-year-old woman with RA is expected to live for 4 years less than a 50-year-old woman without RA.49 Patients with RA have a significantly increased risk of ischaemic heart disease. Heart disease is the principal reason for an approximately 60% increased mortality risk in RA.50 However, other factors such as infection associated with aspects such as comorbidity, including lung disease, extra-articular manifestations of disease, reduced white cell count and corticosteroid use, also contribute.51,52

Burden of illness

Early in disease indirect costs exceed costs due to health-care utilisation and medication (direct costs) by twofold.53 It is also clear that informal caregivers shoulder a considerable burden in terms of forgone paid employment, leisure activity and personal health.54 Inevitably, in a disease characterised by chronic pain, discomfort and physical impairment, the burden on individuals and families is increased. Medication costs, especially in those treated with biologic agents such as TNF inhibitors, account for a majority of the direct costs of RA.55 Some drug intervention studies have shown reduced work absence with aggressive treatment strategies,56 although only one-third of employed patients cease work because of disease and, unsurprisingly, manual workers are much more likely to stop work.57 It is estimated that the total costs of RA to the UK economy is between £3.8 and £4.8 billion.6

Current service provision

Services for patients with RA have been reviewed in detail in a recent report by the NAO.6 Diagnosis and management of RA is led primarily by consultant rheumatologists employed by acute hospital trusts. People who may have RA often seek help late and may suffer owing to delayed treatment and referral. There are around 460 consultant rheumatologists in England, giving a ratio of 1 : 100,000 rheumatologists per head of population (the ratio in Wales is 1 : 106,000). Consultants are supported by specialist nurses and the NAO census identified 377 specialist rheumatology nurses in England. Considerable variations and deficiencies in service provision were identified by the NAO. Specific recommendations for improving services were made by the NAO in the following areas:

  • timely diagnosis and treatment
  • better integration between primary and secondary care services
  • improved holistic care including strategies to improve self-management and providing support for maintaining employment.

Description of the technologies

Five intervention technologies are considered in this report. Three are TNF inhibitors (ADA, ETN and IFX), and one each a T-cell costimulation modulator (ABT) and a selective CD20 B-cell depleting agent (RTX). The technologies are described below. Licensed indications and relevant NICE guidance are detailed in Table 1.

TABLE 1. European Union licensed indications related to RA for the five technologies and relevant NICE guidance.

TABLE 1

European Union licensed indications related to RA for the five technologies and relevant NICE guidance.

Tumour necrosis factor inhibitors

Adalimumab

Adalimumab is a recombinant monoclonal antibody, made from human peptide sequences, which neutralises the biological functions of tumour necrosis factor alpha (TNFα) by binding to TNF cell-surface receptors. ADA is licensed for use in RA, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease.

Etanercept

Etanercept is a combination protein consisting of the extracellular portion of two TNFα receptors (75-kDa TNF receptors) combined with a human fragment crystallisable (Fc) portion of the human immunoglobulin G1 (IgG1). ETN inhibits TNFα activity by binding soluble and cell-bound TNFα with high affinity and by competing with natural TNFα receptors. ETN is licensed for use in RA, psoriatic arthritis, psoriasis and ankylosing spondylitis.

Infliximab

Infliximab is a recombinant chimeric human–murine monoclonal antibody that binds soluble and membrane-bound TNFα thereby, inhibiting the functions of TNFα. IFX is licensed for use in RA, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis.

Other tumour necrosis factor inhibitors

Certolizumab pegol has been granted a marketing authorisation in the European Union (EU) for the treatment of moderate-to-severe RA. It is administered by subcutaneous injection. Certolizumab pegol was the subject of a separate NICE single technology appraisal (STA),58 with guidance published in February 2010. Golimumab is currently being assessed by the European Medicines Agency. A positive opinion has been given for the granting of marketing authorisation in RA. Golimumab has been referred to NICE, but the appraisal has been suspended because the manufacturer is not in a position to submit evidence to NICE.

Special precautions for use of tumour necrosis factor inhibitors

TNFα is a key component of host defence against Mycobacterium tuberculosis (MTB), especially by forming granulomas and preventing dissemination of mycobacteria.59,60 Inhibition of TNFα increases the risk of MTB and other granulomatous diseases, such as those due to Listeria monocytogenes (a bacterium associated with food-borne diseases) and Histoplasma capsulatum (a fungus which, in endemic areas, causes lung disease in people with a compromised immune system). Recommendations for screening patients for tuberculosis (TB) before treatment have been published.61 In the UK this is done most commonly by taking a medical history focusing on TB and a pre-treatment chest radiograph. Some centres also perform a tuberculin skin test,62 although interpretation of such tests is complicated by the UK's previous vaccination programme for TB prevention and also the fact that many patients with RA respond poorly to tuberculin (possibly because of current immunosuppressive therapy but also because of the disease).63

Routine monitoring of blood tests is not necessary for patients taking TNF inhibitors, but is needed for concomitantly used DMARDs such as MTX. TNF inhibitors can induce anti-nuclear 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.64

Other technologies

Rituximab

Rituximab is a chimeric monoclonal antibody which binds the CD20 cell surface marker found on B lymphocytes and depletes these cells. CD20 occurs on normal and malignant B lymphocytes (as in non-Hodgkin's lymphomas). Normal plasma cells, an important component of host defence, and haematopoietic stem cells do not carry CD20. RTX is licensed for use in RA, non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. A small number of cases of progressive multifocal leucoencephalopathy, a rare but usually fatal demyelinating brain disease, have been reported in RA patients following RTX treatment.65

Abatacept

Abatacept is a fusion protein consisting of CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) linked to a modified Fc portion of the human IgG1. ABT works by blocking activation of certain populations of T lymphocytes. ABT is currently licensed for use only in RA.

Tocilizumab

Tocilizumab was the subject of a separate NICE STA,66 with guidance published in August 2010. This guidance is likely to have a key impact on the treatment pathways considered in this review. TOC is a humanised monoclonal antibody that inhibits the activity of the cytokine interleukin-6 (IL-6). In the EU it is licensed for use only in moderate-to-severe RA patients who are intolerant, or have responded inadequately, to one or more DMARDs or TNF inhibitors. The drug is recommended for use in combination with MTX, but may be used alone in patients intolerant of MTX or for whom it is contraindicated. TOC is given by intravenous (i.v.) infusion over 1 hour once a month indefinitely.

Disease-modifying antirheumatic drugs, biologics, treatment sequences and combinations

Rheumatoid arthritis is characterised, in many patients, by an excellent initial response to a DMARD with subsequent loss of response with time. Most randomised trials are of a relatively short duration (typically less than 12 months) and do not study a treatment pathway. Trials of DMARDs sequences are increasingly common.25,67,68 Remission is possible in early disease with MTX alone or in combination with other agents such as sulfasalazine, HCQ, CyA and TNF inhibitors. The optimal sequence is yet to be determined, and perhaps the choice of drug is not relevant, but the key to successful management appears to be regular patient review with a focus on optimal disease control.

The NICE RA guidance is consistent with this approach, although recent trials indicate that early use of MTX in combination with a TNF inhibitor provides better outcomes.25,69 NICE recommends that TNF inhibitors are used only in those not responding to MTX and another DMARD. Delayed addition of a TNF inhibitor need not necessarily compromise medium-term outcomes23,25,69 and may be justified on health-economic grounds.

What steps should be taken when a first TNF inhibitor and several DMARDs including MTX fail? This technology assessment report sets out to examine clinical effectiveness and cost-effectiveness evidence from available randomised controlled trials (RCTs), observational studies and economic evaluations. A small survey conducted as part of this technology assessment on a convenience sample of consultant rheumatologists in the West Midlands indicated considerable variability in approach for patients who fail a first TNF inhibitor. The most common suggested approaches were to consider a second TNF inhibitor or RTX (in combination with MTX). Further details of this survey can be found in Appendix 11.

There are many and increasing permutations of treatment sequences. Combinations of biologic agents are not licensed and where combinations have been tried there is an increased risk of serious infections. Potential drug toxicity of newly licensed agents is an important unknown. Other considerations include practical matters to do with drug delivery such as i.v. or subcutaneous administration and availability of infusion facilities. Patients with RA tend to be risk averse70 and strategies mandating targeted disease control in late ‘stable’ RA are commonly resisted by doctors and patients.71 However, in those with active and progressive disease new therapies are needed. This review seeks to explore some aspects of these uncertainties as determined by a protocol agreed with NICE and interested parties.

Degree of diffusion and anticipated costs

The number of RA patients currently being treated with TNF inhibitors is unknown. By July 2009, 12,626 patients who started treatment with a TNFα inhibitor were registered with the British Society for Rheumatology Biologics Registry (BSRBR). This register has stopped recruiting patients with RA starting ADA, ETN and IFX. So far 2,876 (23%) have ceased taking the first prescribed TNFα inhibitor and switched to a second TNFα inhibitor [1,881 switched owing to the lack of efficacy and 995 because of an an adverse event (AE)]. Of these the mean and maximum observed duration of treatment with a second TNFα are currently 18 months and 64 months, respectively. By August 2009 the BSRBR had registered 442 patients treated with RTX from a target of 1,100.72

The drug costs of biologic agents are similar for the agents given by subcutaneous injection at around £9,000 per annum. Costs of i.v. administered drugs vary depending on patient weight and frequency of treatments courses (with RTX). Likely drug costs for these agents range between £7,000 and £10,000 per annum.

© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation
Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation.
Health Technology Assessment, No. 15.14.
Malottki K, Barton P, Tsourapas A, et al.
Southampton (UK): NIHR Journals Library; 2011 Mar.

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