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We read with interest the article by van Vollenhoven et al.1 In short, they report on 31 patients with rheumatoid arthritis (RA), 18 of whom used etanercept (ETA) first and then switched to infliximab (IFX)in most part because of inefficacy, and 13 patients who used IFX first and changed to ETA mostly owing to adverse events. They suggested using the other tumour necrosis factor (TNF) inhibitor when one of them fails. Although, in general, agreeing with their findings, we would like to present our experience which is somewhat different from theirs and to discuss the possible reasons for this.
We set up an IFX registry at the Hospital for Special Surgery in February 2000, with the start of IFX infusions. The registry collected prospective data on all the patients with RA who started treatment with IFX, and followed up them every 2 months until May 2001. All patients completed questionnaires about their RA history, treatment, and functional disability (modified Health Assessment Questionnaire (mHAQ)) at baseline and every 2 months thereafter. A 42 joint count for tender and swollen joints was performed at each visit. Patients were telephoned 3–5 days after infusions and asked about reactions while at home.
The availability of ETA before the approval of IFX and the fact that use of ETA did not require concomitant methotrexate has resulted in the treatment of more patients with RA with ETA before trying IFX. However, after failure of ETA, several patients changed treatment to IFX. We compared response to treatment, adverse events, and discontinuation rates between patients for whom ETA had failed before IFX treatment (ETA-F) and patients who had not used ETA before—that is, etanercept-naive (ETA-N).
Eighty eight patients were treated with IFX between February 2000 and May 2001 (77 women, mean (SD) age 61 (12.1) years, mean (SD) RA duration 13.4 (9.8) years, failed DMARDs 2). In 37 (42%) patients ETA had failed before IFX was introduced. There was no difference in age, disease duration, and number of failed DMARDs between ETA-F and ETA-N patients. Sixteen ETA-F and 10 ETA-N patients were excluded from the analysis owing to an insufficient number of data points. mHAQ, pain scores, and morning stiffness improved significantly in ETA-N patients, whereas no improvement was noted among the group of ETA-F patients, in the first year after they were receiving IFX. Six ETA-F and seven ETA-N patients discontinued treatment after 4 and 5.7 months, respectively. No significant difference in the number of adverse events was found between ETA-F and ETA-N patients.
We also analysed the functional change and rate of adverse events among patients with RA treated with IFX for those receiving concomitant methotrexate (MTX-R) and those not (MTX-NR). Baseline age and disease duration of MTX-R and MTX-NR patients were similar. IFX treatment was discontinued in 15/42 (36%) MTX-R subjects and 12/46 (26%) MTX-NR subjects. After an average of 6.7 months’ follow up 40/61 subjects experienced 96 adverse events (AEs) over a total of 648 infusions; 16/27 (59%) MTX-NR subjects had 46 AEs, compared with 24/34 (71%) MTX-R subjects who had 50 AEs (p = 0.51). Most of these AEs were minor and none resulted in IFX discontinuation. There was no difference in mHAQ, pain score, swollen and tender joint counts between the MTX-R and MTX-NR groups after 6 months of treatment.
Our clinical experience demonstrates a better clinical response to IFX among ETA naive patients. Based on our data, we would suggest that if ETA fails there might not be a substantial benefit in trying IFX later on. Also, we did not note any difference in the rates of discontinuation or AEs, or response to treatment between MTX-R and MTX-NR patients beyond 6 months of IFX treatment.
We are limited by the number of our patients, just as van Vollenhoven et al were. We also do not have data for patients who switched from IFX to ETA because of the shortage of ETA at the time of our study. These results may reflect a population of refractory patients with RA who have more severe disease (patients for whom multiple DMARDs had failed) and are generally difficult to manage, or who are non-anti-TNF responders. Analysis of ETA-F patients who respond to IFX may show a subgroup who will benefit from different anti-TNF formulations. Given the cost of anti-TNF drugs, larger groups should be studied to determine the characteristics of patients who might benefit from a trial of another anti-TNF agent when one has already failed.
We genuinely appreciate Drs Yazici and Erkan’s interest in our paper.1 The observations they report based on their own infliximab registry are very interesting indeed. In that registry, patients for whom etanercept treatment had previously failed responded less well to treatment with infliximab than etanercept-naive patients. This is not, in itself, a contradiction to our published report, the gist of which was that patients can have meaningful and significant responses to infliximab even if they failed to respond to etanercept—without making a direct comparison with the results seen in etanercept naive patients. However, it would be of interest to know more details about Drs Yazici and Erkan’s patient group.
For instance, the fact that 15 of 21 patients who were said to be “non-responders” continued treatment with infliximab suggests that some measure of improvement was none the less achieved. We have previously published data showing that a sharp distinction between “responders” and “non-responders” is an artefact and that responses in fact are normally distributed.2
Yazici and Erkan also suggest that infliximab with or without concomitant methotrexate provides similar clinical results. In our own database only a few patients received infliximab without concomitant methotrexate so we cannot provide any data bearing directly on this issue. We do note, however, that the important radiological benefits of treatment with infliximab have only been documented in patients receiving background methotrexate.3 Thus, we continue to favour this combination when possible.