Persistent neutralizing antibodies abolish the interferon ß bioavailability in MS patients
Bertolotto A, Gilli F, Sala A, Capobianco M, Malucchi S, Milano E, Melis F, et al.;
Commented by , 21 Mar 2003
Background
Clinical studies have suggested an attenuation of interferon b (IFNb) treatment effect by IFNb neutralizing antibodies (NAb). The significance of these observations is still not clear, and it has been concluded that treatment should be based on clinical grounds alone.
The practical clinical problem in this regard is the long observation period before treatment evaluation can be made. The current study takes advantage of estimating the bioavailability of IFN indirectly by measuring the IFN induced protein MxA.
In this way the authors assesses the changes in biologic response to INFb treatment, which might be a more accurate measurement with regard to treatment effect.
Aim
To evaluate changes in MxA expression and to assess the biologic response to the three INFb formulations available for the treatment of MS.
Methods
A PCR method was used to quantify MxA mRNA in peripheral blood mononuclear cells of 92 patients with MS treated with recombinant INFb (22 Avonex, 53 Rebif, and 17 Betaferon). A group of 99 treatment naïve MS patients and 17 healthy volunteers were used as controls.
NAb were tested against the type of IFNb for individual patients and revealed three categories of patients: NAb negative (NAb -), persistent NAb positive (NAb +, ³ 2 consecutive samples), and isolated NAb+ (one positive sample).
Results
Of the 92 INFb-treated patients, 15 (16%) were persistent NAb+, 68 (74%) were NAb- and 9 (10%) were isolated NAb+. MxA mRNA levels were comparable between treatment naïve MS patients and healthy volunteers.
Mean MxA mRNA expression in INFb-treated patients was 11-fold higher than the level observed with treatment naïve patients. A sharp induction of MxA mRNA was observed in 75 (81,5%) INFb-treated patients and 65 of these were NAb-. MxA mRNA was unchanged in 17 (18,5%) INFb-treated patients and 12 of these were persistent NAb+.
There was a significant difference between MxA mRNA expression in NAb- and isolated NAb+ patients compared with persistent NAb+ patients. In patients with high NAb titers, bioavailability was abolished. There was no difference between the three INFb products in bioavailability 12 hours after injection.
Discussion
The study demonstrates that both higher NAb titers as well as persistent presence of NAb were correlated with bioavailability of INFb, as observed by a decrease in MxA mRNA expression. In this way the study argues for a simple relationship between persistent NAb+ patients and reduced clinical effect of INFb.
An important drawback of the study is the lack of clinical data. In this regard other explanations for reduced bioavailability should be mentioned, which could confound results (e.g. binding antibodies, diminished INFb-receptor expression, increased concentrations of soluble circulating INFb receptors).
Furthermore, the authors find no difference in bioavailability of the three INFb products, although difference in NAb was seen in several clinical trails, which again could be explained by differences in measurement standards (e.g. assay method, definitions of positivity to NAb).
It is clear that we need more data to evaluate the clinical significance of NAb and MxA in MS, but bioavailability seem to be an interesting measure, in order to evaluate early treatment efficacy of INFb.