Reply to Freedman and Burks

Doctors Freedman and Burks have commented on the European Guidelines on the use of anti-IFN-b antibody measurements in multiple sclerosis [1]. Our search strategy included published data up to September 2004. Some new and as yet unpublished data from the authors databases were included to address issues not answered by published data, thus making the guidelines as up to date as possible. The observation that IFN-b 1a s.c. antibody development catches up with IFN-b 1b s.c. has been corroborated in extended studies [2,3]. It is obvious from the results of the Danish Nationwide IFN-b Study that more frequent administration (once versus 3 times weekly) of IFN-b 1a s.c. 22 lg induces NAbs in a higher proportion of patients [2]. There is are no data comparing IFN-b 1a s.c. 44 lg once weekly and 3 times weekly. Regarding the difference in immunogenicity between IFN-b 1a s.c. 22 lg and IFN-b 1a s.c. 44 lg no statistical difference were found in the PRISMS-4 study between the two groups that were initially treated with placebo and subsequently crossed-over to either IFN-b 1a s.c. 22 lg 3 times weekly or IFN-b 1a s.c. 44 lg 3 times weekly [4]. A possible explanation of the apparent difference between IFN-b 1a s.c 22 lg and 44 lg in the 2 years PRISMS study [5] is that circulating IFN-b was present in the plasma from patients treated with the higher dose, because less strict adherence to a 24 h interval between IFN injection and blood sampling was applied in the early trials of IFN-b [6]. This would tend to make the rate of NAb positive patients in the high dose group falsely low. The guidelines recommend that NAb testing should be made in specialized laboratories. There is no statement that the authors could not agree on a standardized NAb assay . The guidelines give a clear statement as to which methods for NAb detection should be used and how to calculate the NAb titre. As these methods include cell or viral cultures it seems justified to recommend that test should be performed in dedicated and experienced laboratories. The difference between loss of bioactivity and loss of measurable bioactivity seems to be a semantic subtlety. We do not know how to assess bioactivity other than measuring it. In fact there is data demonstrating a correlation between bioactivity and the degree of clinical response to IFN-b in MS [7]. Furthermore, use of the bioactivity marker MxA yields a nearly 100% sensitivity and specificity for IFN-b treatment when compared with untreated patients and healthy controls [8], and the expression of MxA mRNA seems to vary in parallel with other genes induced by IFN-b [9,10]. The suggestion of employing the EMEA protocol for NAb assay is only based on class IV evidence and, hence, is not a class A recommendation but a good practice point. Regarding the class of evidence for NAb effects we have defined studies of 3 years or more 1⁄4 class I, studies of 2–3 years 1⁄4 class II, and studies of <2 years 1⁄4 class III. As both the Rudick and Durelli studies were of 2 years duration they were correctly classified as class II. Randomization based on the primary endpoint of NAb development would only be possible if patients who became positive were split into continued versus no treatment groups. As this would require continuing patients on a treatment that is not working on clinical and biomarker outcomes and another group who would normally be switched to have alternative treatment to have placebo – this would not be ethical. As there are no discernable differences in baseline characteristics between patients developing NAbs and those who do not, there are no known biases in the randomization in the current studies. The only reason why there is still discussion about the impact of NAbs on the therapeutic effect of IFN-b is the delay in development of clinically relevant NAbs until 9–15 months after initiation of therapy which makes it almost impossible to show an effect in short-term studies of 2 years and less, particularly if the anytime positive, always positive definition for NAb positivity is applied. Secondly, the modest effect of INF-b on relapses and, in particular, on disease progression makes it difficult to show the disappearance of this relatively weak effect. In fact, an effect on disease progression was not shown in the pivotal INF-b 1b trial and hence, it is difficult to show disappearance of a non-existing difference [11]. Therefore, it was remarkable that it was possible to show an effect of NAb’s on disease progression in the 4-year extension of the dose comparison study of INF-b 1a intramuscularly 30 lg and 60 lg once weakly despite that only 1.8% of patients receiving 30 lg and 4.8% of patients receiving 60 lg INF-b 1a became NAb positive [12]. The majority of Dr Burks comments have already been answered in the reply to Dr Freedman’s letter. However, we would like to comment on the cost-effectiveness of NAb testing. The guidelines are European guidelines on the use of measurement of anti-INF-b antibodies, and in Europe NAb testing is available in many countries either free or at a cost of about 100 €. Preventing one single patient from receiving a treatment without bioactivity of a cost of >10 000 € per year makes it possible to test 50 patients for each year of wasted therapy. As up to 40% of patients, depending on the INF-b preparation, develop NAbs and approximately half of these develop NAbs in titres that abolish all bioactivity the calculation of cost effectiveness is very much in favour of NAb testing. The question may reflect differences between Europe and North America regarding accessibility and costs of NAb testing. However, themost serious problemwith not testing forNAbs is the ethical issue.We find it a serious ethical problem to go on treating patients with INF-b without testing for NAbs knowing that a considerable proportion of the patients do not have any benefit from the treatment due loss of INFb bioactivity caused by NAbs. We recommend testing for NAbs in patients, who have been NAb-negative for the first 24 months of therapy, if these patients show increased clinical activity. The definition of increased disease activity reflects the inherent problem in defining non-responders. There are no generally agreed definition of a non-responder to INF-b treatment but whatever definition the single physician may use it is recommended to resume testing in patients who become non-responders, as NAb is one