However, there are a number of areas in which caution is required. First, the external validity of the findings to current therapeutic practice should be considered. As stated above, they did not include etanercept, which, for example, is the most popular used anti-TNF agent in the UK. Indeed, as the authors argue based on biological principles, this agent may not be expected to carry the same risk. Second, the dose of infliximab in standard RA regimens is typically 3 mg/kg; in the trials evaluated there was only one malignancy (a lymphoma) in a patient treated with this dose of infliximab.
Third, and of greater concern, is the malignancy rate in the control arms, which was unexpectedly low. Among 1512 comparison arm patients, followed for what would appear to be an average of 34 weeks, there was only one malignancy, excluding the two basal cell carcinomas. In a typical RA population, or indeed a general population sample of this age group, one might expect an incidence of around 8/1000 per year, which is at least eight times that seen in the comparison arm patients and is of the same order of magnitude as that seen in the anti-TNF arms of the trials. Does the threefold increased risk reflect an unexpectedly low rate of cancer in the placebo arms rather than a genuine increased risk from anti-TNF therapy? It is not clear why the rate should have been so low. If low-risk patient selection were a factor, then this should have operated equally in the anti-TNF group. There is, however, a possible explanation based on the differential dropout between the studies following entry into the trials. Typically, all patients entered into these explanatory RCTs are, to varying extents, screened to exclude pre-existing malignancy, for example with chest radiography. Thus, in such patients there is a 'telescoping' of ascertainment of malignancy before study entry, with the consequence that fewer new malignancies will be identified in the early post-trial entry period. As the authors acknowledge, in their meta-analysis four out of the nine trials had a higher dropout in the placebo arms, meaning that more patients withdrew from follow up sooner. Given the reduced risk (as outlined above) during the early follow-up periods, this would lead to a bias toward detection of malignancy in the anti-TNF arms during the later periods of follow up. Although all malignancies could have been captured by the US Food and Drug Administration beyond the end of the trial, it is less likely that the placebo arm patients will have their malignancies spontaneously reported once they enter the unblinded phase.
Of the 26 malignancies in the anti-TNF arms, 10 were lymphomas. The possibility that such therapy might increase lymphoma risk was raised previously , although it has been difficult to disentangle the risk from the therapy from the increased risk in patients with severe RA [3, 4]. Indeed, it has been argued that by reducing inflammatory activity, anti-TNF agents might have the ability to reduce lymphoma risk . It is perhaps also surprising there were no lymphomas in the comparison patients, given the previously reported increased risk, especially in those with severe disease treated conventionally . However, using randomized trials, the confounding effect of severity should have been allowed for, and so these data do raise concerns about an increased risk for this tumour that will require longer term follow up of much larger cohorts.
The risk for infection was less marked than that for malignancy in the analysis. Serious infections after randomization might be assumed to be solely due to a drug effect. However, serious infection is based on hospitalization or intravenous antibiotic use, and the threshold for these interventions might differ both between trials and between treatment arms within a trial; if an individual has a good response to the drug, then there may be a lower threshold for admission to hospital with infection. Thus, in comparison with malignancy, it is much harder to standardize the recording of infections across the different trials. There were 35 serious infections/1000 treated anti-TNF patients, which equates to around 52/1000 person-years (or less, allowing for loss to follow up). It is reassuring in terms of external validity that this rate is broadly similar to those reported by two recent national register studies from Germany (infliximab rate 62/1000 person-years)  and the UK (infliximab 55/1000 person-years, adalimumab 52/1000 person-years) .