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Several serious reactions linked to TNF-alpha inhibitors

Tumour necrosis factor alpha ( TNF-alpha ) is a cellular protein produced by the immune system and is an important mediator of many diseases, including inflammatory arthritis and inflammatory bowel disease.
Currently, three tumour necrosis factor alpha blocking agents are registered in Australia: Infliximab ( Remicade ), for the treatment of Crohn's disease, rheumatoid arthritis and ankylosing spondylitis; Etanercept ( Enbrel ), for rheumatoid arthritis, polyarticular juvenile chronic arthritis, psoriatic arthritis and ankylosing spondylitis; and Adalimumab ( Humira ), for rheumatoid arthritis.

While extremely effective, TNF-alpha inhibitors are associated with several serious reactions.
These include:

· Hypersensitivity reactions - immediately post-injection or delayed;

· Serious and life-threatening infection and sepsis;

· Recrudescence of tuberculosis and other granulomatous diseases;

· Reactivation of hepatitis B;

· Malignancy, including lymphoma;

· Haematological reactions such as pancytopenia and aplastic anaemia;

· Autoimmunity - eg, drug-induced lupus;

· CNS reactions, including demyelinating disorders and seizures;

· New-onset heart failure or worsening of advanced heart failure.

ADRAC ( Adverse Drug Reactions Advisory Committee ) has received 319 reports involving TNF-alpha inhibitors since 2000. The more serious of these are: malignant melanoma ( 3 reports ), lymphoma ( 5 ), tuberculosis ( 4 ), pneumonia/lower respiratory tract infections ( 23 ), sepsis ( 10 ), lupus or lupus-like syndrome ( 22 ) and anaphylaxis ( 9 ).

According to Medicare Australia statistics, 57,846 prescriptions for the three TNF-alpha inhibitors combined have been issued for the treatment of rheumatoid arthritis since 2000.

Given their mechanisms of action, it is possible that the use of TNF-alpha inhibitors may predispose patients to an increased risk of malignancies or accelerate their development.

A meta-analysis of randomised trials of Infliximab or Adalimumab in rheumatoid arthritis found that malignancies developed in 0.9% patients treated with Infliximab or Adalimumab, compared with 0.2% patients given placebo. The risk of malignancies was not different from placebo with low dose TNF-alpha inhibitors but was 4 fold greater with high doses of Infliximab or Adalimumab.
An increased risk of malignancies has also been reported for Etanercept.

The Australian Product Information for these medicines advises prescribers that caution should be exercised when considering TNF-blocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy.

The meta-analysis also showed a 2-fold increased risk of serious infections with TNF-alpha inhibitors, regardless of dose. Patients receiving TNF-alpha inhibitors should not receive concurrent vaccination with live vaccines and consideration should be given to screening patients for pre-existing infections, particularly hepatitis B and tuberculosis, prior to their use.

Source: Australian Adverse Drug Reactions Bulletin, 2007