Anti-tumour Necrosis Factor Alpha (anti-TNF-alpha)

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

Biological agents targeting inflammatory cytokines such as tumour necrosis factor alpha (TNF-alpha) have been licensed for a variety of inflammatory conditions, particularly rheumatoid arthritis (RA). They are expensive drugs with a potential for serious toxicity. Selection of patients is therefore an important issue.The cytokine inhibitors affecting TNF-alpha currently available are adalimumab, etanercept and infliximab.

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TNF-alpha is an inflammatory cytokine or pro-inflammatory mediator which, when present in excessive concentrations, is responsible for the destructive inflammatory processes that occur in, for example, articular cartilage and bone in RA. Agents that inhibit the action of TNF-alpha might thus be expected to modify the inflammatory disease process.

  • Adalimumab is an anti-TNF-alpha recombinant human IgG1 monoclonal antibody.[1]
  • Etanercept is recombinant human TNF receptor fusion protein (consisting of p75 TNF-alpha receptor and human IgG) which inhibits the binding of TNF to its cell surface receptor.[2]
  • Infliximab is a chimeric anti-TNF-alpha monoclonal antibody.[3]

It is hoped that the high cost of disease-modifying drugs will prove to be balanced by savings from the benefits of treatment (reduced need for surgery, reduced need for other treatments, reduced care needs, and improved longevity and quality of life). Such benefits have not yet been confirmed and the use of these drugs is careful and highly selective. They should be used according to appropriate guidelines and only with specialist supervision.

Rheumatoid arthritis

National Institute for Health and Clinical Excellence (NICE) guidance[4] and joint guidelines from the British Society for Rheumatology and British Health Professionals in Rheumatology[5] are available.

  • Rituximab plus methotrexate or abatacept plus methotrexate are the first-line option for severe active RA in patients who have had an inadequate response to, or have an intolerance of, other disease-modifying anti-rheumatic drugs (DMARDs), including at least one TNF inhibitor. However, if either of these combinations fails, adalimumab, etanercept and infliximab can be offered as treatment options - each in combination with methotrexate.
  • As second-line options, adalimumab and etanercept can be used as monotherapy if methotrexate is contra-indicated or withdrawn because of an adverse event.
  • Treatment should be monitored using the Disease Activity Score-28 (DAS28) calculator and discontinued after 6 months if there is inadequate response to treatment .[6]
  • One study found a reduction in the incidence of cardiovascular disease in patients with RA taking TNF-alpha antagonists.[7]

Juvenile arthritis

Etanercept is recommended by NICE for juvenile idiopathic arthritis in children aged 4 to 17 years with at least 5 joints affected and whose condition has not responded adequately to methotrexate (or who have been unable to tolerate methotrexate).[8]

Psoriatic arthritis

NICE guidance was issued in August 2010.[9] This states that:

  • Etanercept, infliximab and adalimumab can be used for adults with active and progressive psoriatic arthritis, providing the following criteria are met:
    • The patient has peripheral arthritis with three or more tender joints and three or more swollen joints
    • The arthritis has not been helped by adequate courses of at least two standard DMARDs, either administered individually or together.
  • Treatment should be started with the cheapest drug (this will vary depending on drug administration costs, the dose and product price per dose).
  • Treatment should be discontinued if the arthritis does not respond adequately, using the Psoriatic Arthritis Response Criteria (PsARC),[10] at 12 weeks unless the patient's psoriasis starts to improve, in which case they should be referred to a dermatologist.

Psoriasis

Etanercept is used for severe psoriasis refractory to at least two other systemic treatments and photochemotherapy. NICE guidance was issued in 2006.[11] It recommends that etanercept be offered to adults with severe plaque psoriasis when:

  • Other systemic treatments and photochemotherapy have not worked (usually ciclosporin and methotrexate).
  • Intolerance of other standard treatments.
  • Contra-indications to other standard treatments.

Etanercept should be withdrawn if the response is not adequate after 12 weeks.[11]

Ankylosing spondylitis (AS)

NICE guidance is in progress on the use of adalimumab, etanercept and infliximab.[12]

Etanercept and infliximab are currently licensed for use in severe AS not responding to conventional treatment.

Guidance from the British Society for Rheumatology is available with dosage regimens, guidance on diagnosis and selection for treatment as well as evidence for the treatment rationale.[13] There are measurable benefits with spinal disease from using either drug alone but not from combining with other drugs. It takes about 6 to 9 weeks to show benefit. A systematic review and economic evaluation of all 3 drugs showed equal and significant clinical effectiveness (12-24 weeks of treatment).[14] Longer trials were called for to assess cost-effectiveness in AS.

Crohn's disease

Infliximab and adalimumab have been shown to have benefits in severe active Crohn's disease.

NICE guidance recommends their use in adults with Crohn's disease who meet the following criteria:[15]

  • The Crohn's disease should be severe and active. This is defined as disease in which there is very poor general health and one or more symptoms such as weight loss, fever, severe abdominal pain and usually frequent loose stools (3-4 or more) pre day. There may be new fistulas or extraintestinal signs of the disease. This normally corresponds to a Crohn's Disease Activity (CDA) index score of 300 or more[16] or a Harvey-Bradshaw score of 8-9 or above.[17]
  • The Crohn's disease is refractory to other drugs (azathioprine, steroids, methotrexate, etc.), patients have been intolerant of these drugs, or there are contra-indications to conventional therapy.
  • Patients for whom surgery is inappropriate.

Anti-TNF-alpha drugs should only be prescribed by clinicians familiar with their use and with the management of patients with Crohn's disease. NICE also recommends that:

  • Treatment should be started with the cheapest drug (this will vary depending on drug administration costs, the dose and product price per dose).
  • Treatment should be continued for 12 months or until treatment fails, whichever is the shorter.
  • The risks and benefits of stopping treatment should be discussed with the patient and restarting treatment should be offered as an option if symptoms recur.
  • Infliximab can be used for patients with active fistulising Crohn's disease who have not responded to conventional treatment. It can also be used in patients aged 6-17 years with severe active Crohn's disease who have not responded to conventional therapy. Treatment needs to be reviewed every 12 months.

AS associated with inflammatory bowel disease (IBD)

5-10% of cases of AS are associated with IBD and an even greater number of patients with AS have subclinical IBD. There is some evidence of benefit in these patients.[18]

NICE guidance is available. This highlights that these drugs are for use usually when other drugs have proved inadequate. It also highlights that they are for initiation and monitoring by specialists and according to guidelines such as those of the British Society for Rheumatology (if not part of a clinical study). This means that GPs are unlikely to have much experience or knowledge of these drugs.

Adalimumab is licensed for:

  • Moderate-to-severe RA when other disease-modifying drugs such as methotrexate have not been effective. It should be given in combination with methotrexate or alone if methotrexate cannot be tolerated or there are contra-indications.
  • Crohn's disease. It is sometimes used on an unlicensed basis in fistulating Crohn's disease in patients unable to tolerate infliximab.[19]
  • Psoriatic arthritis.[9]

Etanercept is licensed for:

  • RA, specifically active RA - either alone or in combination with methotrexate.
  • Psoriatic arthritis.
  • Ankylosing spondylitis (AS).

Infliximab is licensed for:

  • Highly active RA in combination with methotrexate when response to other disease-modifying drugs is inadequate.
  • Psoriasis.
  • Psoriatic arthritis.
  • Crohn's disease.[20]
  • Ulcerative colitis. This is an unlicensed indication but studies have shown some benefit for serious flare-ups of ulcerative colitis not responding to standard treatment,[21] and in AS associated with inflammatory bowel disease.[20]

The trials have been done according to manufacturers' dosage schedules and can vary according to age and indication.

  • Adalimumab is generally given by weekly (or alternate weeks) subcutaneous injection.
  • Etanercept is generally given by once or twice weekly subcutaneous injection.
  • Infliximab is given by intravenous infusion at 6-8-weekly intervals.

Cautions include:

  • Hepatic and renal impairment.
  • Mild heart failure (discontinue if symptoms worsen on treatment).
  • Infections.
  • Possible demyelinating disease.
  • Primary vaccination with live attenuated vaccines, which should be avoided.[22]

Contra-indications include:

  • Women who are pregnant or breast-feeding.
  • Septic arthritis within 12 months.
  • Congestive cardiac failure New York Heart Association (NYHA) grade 4 for infliximab.
  • Demyelinating disease.

These drugs have all been associated with infections (sometimes severe, and including tuberculosis and septicaemia). Nausea, hypersensitivity reactions, worsening heart failure and various blood disorders (anaemia, leukopenia, lymphoma, aplastic anaemia, thrombocytopenia and pancytopenia) have all been reported.[3] Of concern are cases of hepatosplenic T-cell lymphoma reported in adolescent and young adult patients with Crohn's disease treated with infliximab. This rare type of T-cell lymphoma is usually fatal. All of these T-cell lymphomas occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine.[3]

  • Monitoring of the disease and for drug side-effects should be under close specialist supervision.
  • In RA, monitoring should continue on a 6-monthly basis using the DAS28 calculator. Treatment should be discontinued if adequate response is not maintained.
  • In juvenile arthritis, etanercept should be tried for 6 months before stopping and continued for up to 2 years although, again, disease activity and individual response should be taken into consideration.
  • In Crohn's disease, treatment should be continued for 12 months or until treatment fails, whichever is the shorter. Loss of response to anti-TNF-alpha drugs is becoming an increasing clinical problem; the reason for this unknown.
  • In psoriatic arthritis, treatment should be stopped after 12 weeks if there is no adequate response, unless the patient's psoriasis start to improve.
Specialist supervision These drugs are recommended only for initiation and supervision by suitably qualified specialists. This is appropriate, given the conditions being treated and the experience required to monitor these expensive drugs with specific indications and potentially serious adverse reactions. Important considerations before treatment (such as excluding tuberculosis infection and assessing the risk of reactivating a latent infection[23]), awareness of the range of adverse effects and monitoring of the therapeutic benefits are all important aspects of the specialist supervision.[24]

GPs are unlikely to have knowledge or experience of these drugs because they will have been initiated and monitored in specialist centres. It is desirable in such circumstances for communication between specialist and GP to detail what drug is being used, the dosage and regimen being used and adverse effects of which to be aware.[25]

Further reading & references

  • Hyrich KL, Watson KD, Lunt M, et al; Changes in disease characteristics and response rates among patients in the Rheumatology (Oxford). 2011 Jan;50(1):117-23. Epub 2010 Jul 29.
  • Reenaers C, Louis E, Belaiche J; Current directions of biologic therapies in inflammatory bowel disease. Therap Adv Gastroenterol. 2010 Mar;3(2):99-106.
  1. Summary of Product Characteristics (SPC) - Humira® (adalimumab); Summary of Product Characteristics (SPC) - Humira® (adalimumab), Abbott Laboratories Limited, electronic Medicines Compendium, updated February 2011
  2. Summary of Product Characteristics (SPC) - Enbrel®; Summary of Product Characteristics (SPC) - Enbrel® 25 mg powder and solvent for solution for injection (etanercept), Wyeth Pharmaceuticals. electronic Medicines Compendium, updated February 2011
  3. Summary of Product Characteristics (SPC) - Remicade®; Summary of Product Characteristics (SPC) - Remicade® 100 mg powder for concentrate for solution for infusion (infliximab), Schering-Plough Ltd, electronic Medicines Compendium. Updated February 2011
  4. Rheumatoid arthritis - drugs for treatment after failure of a TNF inhibitor, NICE Technology Appraisal Guideline (August 2010)
  5. BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies; British Society for Rheumatology and British Health Professionals in Rheumatology (September 2010)
  6. Disease Activity Score Calculator (Rheumatoid Arthritis),Rheumatology Information Service Europe (2008)
  7. Greenberg JD, Kremer JM, Curtis JR, et al; Tumour necrosis factor antagonist use and associated risk reduction of Ann Rheum Dis. 2011 Apr;70(4):576-582. Epub 2010 Nov 24.
  8. Etanercept for the treatment of juvenile idiopathic arthritis, NICE Technical Appraisal (2002)
  9. Psoriatic arthritis - etanercept, infliximab and adalimumab; NICE Technology Appraisal Guideline (August 2010)
  10. Gladman DD, Tom BD, Mease PJ, et al; Informing response criteria for psoriatic arthritis (PsA). II: Further J Rheumatol. 2010 Dec;37(12):2559-65. Epub 2010 Oct 15.
  11. Etanercept and efalizumab for the treatment of adults with psoriasis, NICE Technology Appraisal (2006)
  12. Ankylosing spondylitis - adalimumab, etanercept and infliximab; NICE Technology Appraisal (May 2008)
  13. Guideline for Prescribing TNF alpha Blockers in Adults with Ankylosing Spondylitis, British Society for Rheumatology (2004)
  14. McLeod C, Bagust A, Boland A, et al; Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation. Health Technol Assess. 2007 Aug;11(28):1-158.
  15. Crohn's disease - infliximab (review) and adalimumab (review of TA40), NICE Technology Appraisal (May 2010)
  16. Thia K, Faubion WA Jr, Loftus EV Jr, et al; Short CDAI: development and validation of a shortened and simplified Crohn's Inflamm Bowel Dis. 2011 Jan;17(1):105-11. doi: 10.1002/ibd.21400.
  17. Best WR; Predicting the Crohn's disease activity index from the Harvey-Bradshaw Index. Inflamm Bowel Dis. 2006 Apr;12(4):304-10.
  18. Rebelo A, Leite S, Cotter J; Association of ankylosing spondylitis and Crohn's disease successfully treated BioDrugs. 2010 Dec 14;24 Suppl 1:37-9. doi: 10.2165/11586220-000000000-00000.
  19. British National Formulary; 62nd Edition (Sep 2011) British Medical Association and Royal Pharmaceutical Society of Great Britain, London
  20. Rudwaleit M, Baeten D; Ankylosing spondylitis and bowel disease.; Best Pract Res Clin Rheumatol. 2006 Jun;20(3):451-71.
  21. Martinez-Montiel MP, Munoz-Yague MT; Biologic therapies for chronic inflammatory bowel disease.; Rev Esp Enferm Dig. 2006 Apr;98(4):265-291.
  22. Visser LG; TNF-alpha Antagonists and Immunization. Curr Infect Dis Rep. 2011 Apr 1.
  23. Recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment, British Thoracic Society (2005)
  24. Ledingham J, Deighton C; British Society for Rheumatology Standards, Guidelines and Audit Working Group. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis. (Update of previous guidelines of April 2001).
  25. Prescribing Advice, General Medical Council; (under P of A-Z ethical section)

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Richard Draper
Current Version:
Last Checked:
20/04/2011
Document ID:
807 (v6)
© EMIS