In this study, we analyzed drug survival in patients switching TNF antagonists for chronic arthritis. Overall, our results show that the probability of retaining a second TNF antagonist is lower than that of retaining the first one. Of further interest, probability of survival was influenced by diagnosis, reason for drug replacement, and perhaps the molecule used.
Measuring the effectiveness of drugs through observational databases has some limitations, such as assignment of treatment, patient selection bias, and the absence of a washout period [19
]. Nonetheless, drug survival can be taken as a sensible indicator of its effectiveness in the clinical setting, and community-based studies that analyze continuation of treatment with different DMARDs are common in rheumatology [20
]. Furthermore, withdrawal rates of DMARDs in observational studies are similar to those reported in clinical trials [25
]. This type of analysis may also demonstrate the effectiveness of new therapies [26
In a study of RA conducted in seven Swedish clinical centers, discontinuation rates at 24 months of infliximab and etanercept were 25% and 21%, respectively, in agreement with our results [12
]. This observation is in contrast with the 0% discontinuation rate reported after 15 months of treatment with infliximab and etanercept in a university clinic in the USA [27
]. Parameters other than efficacy and safety, such as co-morbidity, co-medications [28
], costs, availability of other therapies, patients' and physicians' expectations, and adherence to treatment [29
], are at play. Adherence is also important in this type of analysis. It is a reflection, among other elements, of the patient's compliance [26
], pertinent in the case of molecules with different modes of administration, and of variable costs in the diverse health systems. Whether all these factors explain the dissimilarity in the drug survival of TNF antagonists needs further elucidation. Of note, TNF antagonists have similar survival in the different forms of chronic arthritis.
In a previous study, improvement was reported in 8 of 14 RA patients who switched from infliximab to etanercept or from etanercept to infliximab (6 patients) because of adverse events or lack of efficacy [13
]. In another study, improvement was observed in 20 patients replacing etanercept with infliximab [14
]. The efficacy and safety of four infusions of infliximab in patients failing to respond to etanercept have been described as well [15
]. Finally, improvement in inflammation parameters was seen in 12 of 14 patients switching from infliximab to etanercept in another recent study [16
]. Information regarding switching to or from adalimumab is not available yet. In the present study, efficacy based on evaluation of clinical parameters was not investigated. Instead, effectiveness was assessed as the probability of drug survival in a large number of patients. Our results indicate that switching TNF antagonists may be effective in a selected group of patients.
Older age emerged as a predictor of shortened drug survival. This is not surprising in light of older patients' recognized risk of suffering medication-related problems [29
Unexplained is the lower survival of infliximab when compared to other TNF antagonists, especially when used for replacement therapy. Bias towards the use of new drugs in the most severe or non-responder patients [30
] distorts assessment of efficacy. This bias disappears as the pool of patients completes the exposure to the new agent [31
]. It should be kept in mind that infliximab treatment was started 40 and 50 months before etanercept and adalimumab, respectively. When infliximab was made available, it was first used in the most severe cases, in those patients in whom good drug survival was not very much expected. As other TNF antagonists became available, patients with a less severe disease were offered these treatments, thus improving overall drug survival (Figure ). In addition, availability of other TNF antagonists may have led to early drug discontinuation and replacement with a novel agent. In all probability, discontinuation rates of the new TNF antagonists in clinical practice will increase with the arrival of other therapeutic agents. Also, a key variable among the members of the TNF antagonist class is the route of administration [32
]. Infusion reaction occurs early in the follow-up of patients with infliximab, which cuts the drug survival dramatically, especially if taking into account that, in this case, the initiation and discontinuation date are the same, something very unusual with other preparations. Furthermore, the intravenous route is generally related to more adverse events. Also, patients may have preferences for particular routes, for example, subcutaneous, and so ask the physician for a change, although this was the main reason for discontinuation in only four cases.
Survival estimates of infliximab before and after the marketing authorization of etanercept (p < 0.001).
In our study, in contrast with others, differences in cost were not a major consideration for using one or another TNF antagonist, because of the free, unrestricted access to the drugs, provided to all patients by the National Health System.