Tumour necrosis factor alpha inhibitors. Aust Adv Drug Reactions Bull Volume 25 (Number 6), 23-24, December 2006
Currently, 3 TNFα inhibitors are registered in Australia: infliximab (Remicade) - for the treatment of CD, RA and ankylosing spondylitis (AS); etanercept (Enbrel) - for RA, polyarticular juvenile chronic arthritis, psoriatic arthritis and AS; and adalimumab (Humira) - for RA. ADRAC has received 319 reports involving TNFα inhibitors since 2000. The more serious of these are: malignant melanoma (3 reports), lymphoma (5), TB (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 3 TNFα inhibitors combined have been issued for the treatment of RA 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 metaanalysis of randomised trials of infliximab or adalimumab in RA found that malignancies developed in 29/3192 (0.9%) patients treated with infliximab or adalimumab, compared with 3/1428 (0.2%) patients given placebo. 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. 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 TNFα inhibitor 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 preexisting infections, particularly hepatitis B and TB, prior to their use.
Adverse events with TNF antagonists. Bandolier 2006; 249. Available at: http://www.jr2.ox.ac.uk/bandolier/
Fiddling with the immune system brings dangers, including cancer and serious infections. Trying to measure the rate at which these rare events occur, and whether the rates are different with TNFα inhibitors is hard because of limited numbers. New studies provide at least some insight, and highlight the problems. It is probably best to look at the evidence from randomised trials first, then compare it with evidence from observational studies.
A systematic review and meta-analysis (Bongartz et al – included in this document) used trials of infliximab and adalimumab in RA (etanercept was excluded because of a somewhat different mechanism of action). It examined published material for serious adverse events, used FDA information, and discussed serious adverse events with trialists and manufacturers for clarification. The denominator was the number of patients with at least one dose of drug, and the numerator patients with at least one serious malignancy or infection. Nine trials lasting at least 12 weeks (8 were 6 months to1 year) randomised 5,014 patients.
Malignancy: There were 29 malignancies in 3,192 patients (0.9%) on infliximab or adalimumab, and 3 in 1,428 (0.2%) on placebo; 6 other lymphomas were detected during follow up, but not included in the analysis. The OR was 3.3 (1.2 to 9.1), and the number of patients who needed to be treated for 6 to 12 months with infliximab or adalimumab for one to be harmed was 154 (91 to 500).
Serious infections: There were 126 serious infections in 3,493 patients (3.6%) on infliximab or adalimumab, and 26 in 1,512 (1.7%) on placebo. The OR was 2.0 (1.3 to 3.1), and the number of patients who needed to be treated for 6 to 12 months with infliximab or adalimumab for one to be harmed was 59 (39 to 125).
A series of observational studies come from Sweden (see Askling et al papers in this document), where the mix of TNFα inhibitors was predominantly etanercept and infliximab. These used several sources of information, a prevalent cohort of 53,000 RA patients, an incidence cohort of 3,700 RA patients, and one RA cohort of 4,160 patients treated with TNFα inhibitors. These had approximately 300,000, 13,000, and 10,000 person years of follow up respectively, with average follow ups of 6, 3.5 and 2.5 years per patient. Linkage between different registries and cancer and other registries meant that outcomes could be collected. The entire Swedish population served as a control group for calculation of standardised rates.
Malignancies: Haematopoietic malignancies occurred in 507 patients, at rates higher than the general population. When compared with the prevalent and incident RA cohorts not receiving TNFα inhibitors, patients receiving TNFα inhibitors had a RR of 1.1 (95% CI 0.6 to 2.1). Solid cancers occurred in 3,584 patients, at rates little greater than in the general population. When compared with the prevalent and incident RA cohorts not receiving TNFα inhibitors, patients receiving TNFα inhibitors were little different overall, or when analysed by duration of observation.
Serious infections: This is limited by the small number of TB cases in patients treated with infliximab or etanercept (15, 10 of them pulmonary). Only 4 of these were included in a statistical analysis. The best guess is that TB rates are increased in RA patients treated with TNFα inhibitors.
It is always tempting to dismiss observational studies when they disagree with randomised trials (or meta-analyses of them). This may be hasty, especially when both types of study are well done. It is always worth asking a few questions, especially when dealing with serious, but rare, adverse events. The first question is about size, about the number of events. Because they are rare events, malignancies and serious infections are unlikely to be numerous. If a statistical analysis is based on a handful of events, potential interference from the random play of chance is possible. One meta-analysis, for instance, had 3 malignancies with placebo, and one observational study used 4 and 2 cases of TB to calculate statistics. While on size, observational studies can involve a lot of patients, and here observational studies had up to 4 times as many patient years of observation than did a meta-analysis of randomised trials. Which brings us to time, especially important for adverse events. Some may occur early with treatment, others late, or they can be constant over time. Comparing short with long duration studies can be problematical.
And finally, what treatments are being used? None of the observational studies seemed to include adalimumab, or any other newer agents. So while meta-analyses concentrated on some agents but not others, observational studies reported on a different mix of agents being used in clinical practice. The question, then, is whether like is being compared with like. If there is a lesson here, it is that for serious but rare adverse events, rushing to judgement may not be prudent. If there is an answer, it is that tinkering with the immune system can produce great benefit, but with a risk of something bad happening. Until it can be said for certain who will benefit and who will be at risk, we have to live with that uncertainty.