Tumour necrosis factor alpha inhibitors

Tumour necrosis factor alpha (TNFΑ) 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 TNFΑ 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, TNFΑ inhibitors are associated with several serious reactions.^1,2,3 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 has received 319 reports involving TNFΑ 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 TNFΑ 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 TNFΑ inhibitors may predispose patients to an increased risk of malignancies or accelerate their development. A recent meta-analysis of randomised trials of infliximab or adalimumab in rheumatoid arthritis found that malignancies developed in 29/3192 (0.9%) patients treated with infliximab or adalimumab, compared with 3/1428 (0.2%) patients given placebo.⁴ The risk of malignancies was not different from placebo with low dose TNFΑ inhibitors but was 4 fold greater with high doses of infliximab or adalimumab.⁴ 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 recent meta-analysis also showed a 2-fold increased risk of serious infections with TNFΑ inhibitors, regardless of dose. Patients receiving TNFΑ 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.⁵

Reference

1. Botsios C. Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases. Autoimmunity Reviews 2005; 4:162-70.
2. Khanna D, McMahon M, Furst DE. Safety of tumour necrosis factor-alpha antagonists. Drug Safety. 2004; 27: 307-24.
3. Lu TY. Managing patients taking tumour necrosis factor inhibitors. Aust Prescriber 2006; 29; 67-70.
4. Bongartz T et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA 2006; 295; 2275-2285.
5. Nash PT, Florin THJ. Tumour necrosis factor inhibitors. MJA 2005; 183: 205-208.

Reference
Australian Adverse Drug Reactions Bulletin, Volume 25, Number 6, December 2006