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Anti-TNF therapy

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There are now five anti-tumour necrosis factor (TNF) drugs licenced for use in rheumatoid arthritis. This chapter examines the similarities and differences between the drugs and looks for clues with regard to their rational prescribing. The major difference is between the monoclonal antibody-based drugs and the soluble receptor etanercept. Etanercept exhibits the best drug survival and is also associated with a lower risk of opportunistic infections, particularly tuberculosis. Immunogenicity should explain some of the differences between the different drugs but the lack of standardised assays has hindered this area of research. The optimal approach to the patient who has failed their first anti-TNF remains unclear and awaits appropriate clinical trials. The safety profile of anti-TNFs has become clearer, largely through registry data. There is a small increase in serious and opportunistic infections but there does not appear to be a heightened cancer risk, and cardiovascular risk is probably reduced.

Section snippets

Anti-TNF agents

There are now five TNF inhibitors available for the treatment of RA, three of which are full-length monoclonal antibodies: infliximab, adalimumab and golimumab (Fig. 1 and Table 1). Infliximab is a chimeric protein composed of a murine variable region and human constant region. Golimumab and adalimumab are fully human antibodies, produced using recombinant DNA technology. The fourth agent, etanercept, is a fusion protein of two TNFR2 receptor extracellular domains and the Fc fragment (hinge,

Clinical differences between the anti-TNF agents – do we need five anti-TNFs?

The clinical trial data primarily assessed short-term drug efficacy, protection from radiographic damage and side-effect profiles. In those studies the different drugs appear to be very similar, but a few differences have emerged subsequently, both through studies to optimise treatment efficacy, registries and clinical experience.

Immunogenicity

The clinical significance of the development of anti-drug antibodies (antiglobulins) has yet to be fully understood but these can potentially influence drug efficacy, pharmacokinetics and adverse event profiles. Antiglobulins can form complexes with the target drug resulting in its inactivation or accelerated clearance, which clinically manifests as a requirement for increased drug dosages or a secondary loss of effect. Work in this area has been hampered by the lack of standardised methods for

Switching between anti-TNF agents

Registry data demonstrate that up to 50% of patients will have discontinued a previously effective anti-TNF after 3–4 years, either secondary to adverse effects or lack of efficacy *[26], *[27], [54]. The two options available for these patients are to switch to an alternative anti-TNF or to commence a biologic agent aimed at a different target. The initial encouraging reports for switching to a second anti-TNF came from small studies and case series [55], [56]. There are currently no

Tapering anti-TNF

The efficacy of anti-TNFs is established but the ultimate goal for patients is to gain a drug-free remission which could theoretically reduce potential drug side effects, improve quality of life and reduce overall costs. Although the numbers are small, work in early RA has shown that in some patients it is possible to induce early disease remission with an anti-TNF and later successfully withdraw this treatment *[65], [66]. However, in clinical practice anti-TNFs are most often used in those

Adverse events

Anti-TNF agents have greatly improved the quality of life for many RA patients but there remain concerns regarding the risk of serious adverse events, in particular serious infections and lymphoma. Patients with active RA are already at increased risk of serious complications and the question is whether these agents increase the risk above that of a similar but non-biologically treated RA population. The anti-TNF agents have now been licenced for over 10 years and our understanding of their

Personalised medicine

The ideal for both patients and clinicians would be to optimise and personalise medical care, thereby improving the risk:benefit ratio of the medications prescribed whilst simultaneously reducing costs. We know that approximately one-third of patients will not have a satisfactory response to their first anti-TNF therapy and others encounter side effects. In the coming years, we may come to use demographics, clinical characteristics and probably biomarkers to target the most appropriate agent to

Summary

Five different anti-TNF agents are now available for clinical use, and biosimilar drugs are on the horizon. Although some of these can be used as monotherapy according to their licence, all appear more effective when combined with MTX. Registries suggest that patients remain on etanercept for the longest and infliximab for the shortest time but, in the absence of head-to-head studies it is difficult to make definitive comparisons. However, these data are consistent with immunogenicity studies

References (102)

  • R. Palframan et al.

    Use of biofluorescence imaging to compare the distribution of certolizumab pegol, adalimumab, and infliximab in the inflamed paws of mice with collagen-induced arthritis

    Journal of Immunological Methods

    (2009)
  • A. Finckh et al.

    Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients

    Joint, Bone, Spine: Revue du Rhumatisme

    (2010)
  • J.S. Smolen et al.

    Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial

    Lancet

    (2009)
  • F.B. Pallavicini et al.

    Tumour necrosis factor antagonist therapy and cancer development: analysis of the LORHEN registry

    Autoimmunity Reviews

    (2010)
  • L. Carmona et al.

    Cancer in patients with rheumatic diseases exposed to TNF antagonists

    Seminars in Arthritis and Rheumatism

    (2011)
  • T. Saxne et al.

    Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum

    Arthritis and Rheumatism

    (1988)
  • J. Keffer et al.

    Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis

    The EMBO Journal

    (1991)
  • M.J. Elliott et al.

    Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha

    Arthritis and Rheumatism

    (1993)
  • Merck, Sharp, Dohme Ltd. Remicade, summary of product characteristics....
  • M.E. Weinblatt et al.

    Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

    Arthritis and Rheumatism

    (2003)
  • F.C. Breedveld et al.

    The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment

    Arthritis and Rheumatism

    (2006)
  • Abbott Laboratories Ltd. Humira, summary of product characteristics....
  • L.W. Moreland et al.

    Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial

    Annals of Internal Medicine

    (1999)
  • Wyeth Pharmaceuticals. Enbrel, summary of product characteristics....
  • E.C. Keystone et al.

    Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

    Annals of the Rheumatic Diseases

    (2009)
  • P. Emery et al.

    The effects of golimumab on radiographic progression in rheumatoid arthritis: results of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy

    Arthritis and Rheumatism

    (2011)
  • Merck, Sharp, Dohme Ltd. Simponi, summary of product characteristics....
  • P.J. Mease

    Certolizumab pegol in the treatment of rheumatoid arthritis: a comprehensive review of its clinical efficacy and safety

    Rheumatology (Oxford)

    (2011)
  • E. Keystone et al.

    Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study

    Arthritis and Rheumatism

    (2008)
  • J. Smolen et al.

    Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial

    Annals of the Rheumatic Diseases

    (2009)
  • R. Fleischmann et al.

    Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study

    Annals of the Rheumatic Diseases

    (2009)
  • UCB Pharma Ltd. Cimzia, summary of product characteristics....
  • S. Kozlowski et al.

    Developing the nation’s biosimilars program

    The New England Journal of Medicine

    (2011)
  • CHMP

    European medicines agency guideline on similar biological medicinal products

    (2005)
  • H. Schellekens

    Biosimilar therapeutics-what do we need to consider?

    NDT Plus

    (2009)
  • M.M. Soliman et al.

    Impact of concomitant use of DMARDs on the persistence with anti-TNF therapies in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register

    Annals of the Rheumatic Diseases

    (2011)
  • M.L. Hetland et al.

    Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry

    Arthritis and Rheumatism

    (2010)
  • A. Zink et al.

    Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an observational cohort study: comparison of patients according to their eligibility for major randomized clinical trials

    Arthritis and Rheumatism

    (2006)
  • W.G. Dixon et al.

    Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR)

    Annals of the Rheumatic Diseases

    (2010)
  • Etanercept plus standard therapy for Wegener’s granulomatosis

    The New England Journal of Medicine

    (2005)
  • R.P. Baughman et al.

    Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial

    Chest

    (2005)
  • J.H. Anolik et al.

    Cutting edge: anti-tumor necrosis factor therapy in rheumatoid arthritis inhibits memory B lymphocytes via effects on lymphoid germinal centers and follicular dendritic cell networks

    Journal of Immunology

    (2008)
  • A. Nesbitt et al.

    Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents

    Inflammatory Bowel Diseases

    (2007)
  • M.M. Herenius et al.

    Monocyte migration to the synovium in rheumatoid arthritis patients treated with adalimumab

    Annals of the Rheumatic Diseases

    (2011)
  • B. Scallon et al.

    Binding and functional comparisons of two types of tumor necrosis factor antagonists

    The Journal of Pharmacology and Experimental Therapeutics

    (2002)
  • Z. Kaymakcalan et al.

    Murine model for assessing adalimumab, infliximab and etanercept to prevent polyarthritis

    Annals of the Rheumatic Diseases

    (2003)
  • A. Hess et al.

    Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system

    Proceedings of the National Academy of Sciences of the United States of America

    (2011)
  • J. Augustsson et al.

    Patients with rheumatoid arthritis treated with tumour necrosis factor antagonists increase their participation in the workforce: potential for significant long-term indirect cost gains (data from a population-based registry)

    Annals of the Rheumatic Diseases

    (2010)
  • T. Olofsson et al.

    Decrease in sick leave among patients with rheumatoid arthritis in the first 12 months after start of treatment with tumour necrosis factor antagonists: a population-based controlled cohort study

    Annals of the Rheumatic Diseases

    (2010)
  • K. Bendtzen et al.

    Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab

    Arthritis and Rheumatism

    (2006)
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