Monday, 21 April 2014

MxA levels and interferon-beta response

Can we predict who are responders and non-responders to interferon-beta? #MSBlog #MSResearch

"Interferon-beta is a cytokine (intracellular immune messenger) that binds to its receptors on cells to induce specific biological effects. It is one of the major antiviral cytokines and induces cells to produce a protein called Myxovirus-resistance protein A or MxA that is responsible for viral resistance. The study below shows that the greater average induction of this protein in MSers treated with interferon-beta predicts response to interferons. Neutralizing anti-interferon beta antibodies or NABs is one mechanism for blunting this MxA response; NABs prevent IFN-beta binding to its receptor and inducing the response. Does this mean we can use MxA levels to predict a poor response to IFN-beta? Possibly; a lack of induction or poor induction of MxA once you have been on IFN-beta for several months is predictive of NABs. The test for MxA induction is easier to standardise than NABs so it could be used in this way. What about before you start IFNbeta, can you use MxA to predict who will be a responder or non-responder to IFN-beta? There is evidence that if you have raised MxA levels, and other IFN-beta gene products, prior to starting IFNbeta you are likely to be a non-responder to interferon-beta. In other words if your own immune system is producing interferon-beta you are less likely to respond. Despite the latter information being known for several years and being reproduced by several groups it has not made it into clinical practice. Why? Simply because it has never been validated in large prospective clinical trials. I say this with my tongue in my cheek as several Pharma companies have data sets that can be analysed to see if this observation holds true for their interferon-beta product. However, if you have a blockbuster drug do you want to do anything to complicate and threaten its use or market? We were hoping to prospectively test whether a baseline interferon-beta signature predicts and interferon-beta treatment response as part of our UK OPTIMISE study, but unfortunately, the study was never funded. I still think it is important to be able to predict which MSers are likely to be responders, or non-responders, to interferon-beta. Interferon-beta is a safe drug and responders do very well on the drug. This is why I tell patients in my care that are doing well on interferon-beta (NEDA) to stay on the drug. Why change to another drug that you may not respond to?"


"You may be interested to know that interferon-beta was originally tried in MSers by Larry Jacobs as he thought MS was due to a viral infection. It is interesting that some hypotheses concerning MS never go away."

Serana et al. MxA mRNA Quantification and Disability Progression in Interferon Beta-Treated Multiple SclerosisPatients.PLoS One. 2014 Apr 14;9(4):e94794.

Background: Even though anti-interferon beta (IFNβ) antibodies are the main determinants of IFNβ bioactivity loss and Myxovirus-resistance protein A (MxA) is the most established marker of IFNβ biological activity in IFNβ-treated MSers, their usefulness in the routine clinical practice is still debated. 


Methods: Therefore, 118 MSers naïve for treatment were enrolled for a 3-year longitudinal observational study mimicking the conditions of a real-world setting. In order to evaluate the kinetics of bioactivity loss in blood samples obtained every 6 months after therapy initiation, MxA and interferon receptor isoform/subunit mRNA were quantified by real-time PCR, anti-IFNβ binding antibodies were detected by radioimmunoprecipitation, and neutralizing antibodies by cytopathic effect inhibition assay. Clinical measures of disease activity and disability progression were also obtained at all time points. 

Results: We found that, at the individual-MSer level, the response to IFNβ therapy was extremely heterogeneous, including MSers with stable or transitory, early or late loss of IFNβ bioactivity, and MSers with samples lacking MxA mRNA induction in spite of absence of antibodies. No interferon receptor isoform alterations that could explain these findings were found. At the group level, none of these biological features correlated with the measures of clinical disease activity or progression. However, when MxA mRNA was evaluated not at the single time point as a dichotomic marker (induced vs. non-induced), but as the mean of its values measured over the 6-to-24 month period, the increasing average MxA predicted a decreasing risk of short-term disability progression, independently from the presence of relapses. 

Conclusions: Therefore, a more bioactive treatment, even if unable to suppress relapses, reduces their severity by an amount that is proportional to MxA levels. Together with its feasibility in the routine laboratory setting, these data warrant the quantification of MxA mRNA as a primary tool for a routine monitoring of IFNβ therapy.

CoI: multiple

3 comments:

  1. In light of the arrival of new DMT that are much better than interferons, surely it will be in the cpmpamies interest to know who they can best sell their drug to.

    ReplyDelete
  2. What about response to Copaxone?

    ReplyDelete
    Replies
    1. "What about response to Copaxone?"

      There is work being done on this:

      http://m.neurology.org/cgi/content/meeting_abstract/78/1_MeetingAbstracts/S20.003

      Delete

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