Monday, 26 May 2014

Previous treatments influence fingolimod efficacy

What do you think of natalizumab sticky plaster analogy? #MSBlog #MSResearch

"The following study may alarm some of you; it show that MSers switching from natalizumab to fingolimod had a higher relapse rate than those switching from interferon-beta or glatiramer acetate. What the abstract does not tell you is that the MSers on natalizumab had an average wash-out period of 18 weeks, with a range from 12 to 24 weeks. What this study is documenting is MS rebound post-natalizumab. When you have no wash-out, or minimal wash-out (less than 8 weeks), between your last natalizumab infusion and starting fingolimod you prevent this rebound. This data is therefore not relevant to today's practice. This shows you how scientific publications often lag behind clinical practice."

"Why do you get rebound? That is an interesting question. It means that whatever is causing MS does not go away; it is still in the brain of MSers. By keeping out auto-aggressive cells with natalizumab you prevent them finding and attacking their target. By removing natalizumab you allow these immune cells to traffic back in the central nervous system find what they are programmed to find and attack it. Natalizumab withdrawal is the best and most predictable model of relapse we have in MS, that is human MS. I am sure the cause of MS is to be found by studying this phenomenon more carefully."

"One colleague described natalizumab as sticky plaster; it is fine whilst the sticky plaster is in place, but remove it and all hell breaks lose. This is why I find induction therapies so appealing; they target the peripheral immune response and don't rely on suppressing the immune cell trafficking."



Epub: Baldi et al. Previous treatment influences fingolimod efficacy in Relapsing-Remitting Multiple Sclerosis: results from an observational study. Curr Med Res Opin. 2014 May 15:1-23.

Objective: Fingolimod (FTY) is licensed as a disease-modifying treatment in highly active Relapsing-Remitting Multiple Sclerosis. The aim of the study was to evaluate the efficacy and safety of FTY in a real-life setting and to explore the possible role of clinical and MRI parameters, including previous treatment type, in predicting its efficacy. 


Methods: Clinical and MRI data was collected on 127 MSers assigned to treatment with FTY in six Multiple Sclerosis Centers in Emilia-Romagna, Italy, between August 2011 and June 2013. 

Results: During a mean follow-up period of 10 months (range 1-22), we observed a total of 47 relapses in 39 MSers (30.7%); new T2 lesions or Gadolinium-enhancing (Gd+) lesions were present at follow-up MRI in 32/71 patients (45%). EDSS at the end of the follow-up period was not different when compared to the baseline EDSS. Serious adverse events occurred in 3 MSers (2.4%). A higher proportion of MSers previously treated with natalizumab showed clinical (41%) or MRI activity (54%). Previous treatment with natalizumab increased the risk of a relapse within 30 days (versus immunomodulatory drugs; OR: 4.3; p=0.011) and at survival analysis (versus remaining MSers; HR: 1.9; p=0.046). Study limitations include a small population sample, a short observation period with variable timing of follow-up MRI and different baseline characteristics of MSers previously treated with natalizumab compared to those treated with immunomodulatory drugs.

Conclusions: This study confirms the efficacy of FTY in reducing relapse rate in MSers previously treated with immunomodulatory drugs, while it seems to be less effective in patients discontinuing natalizumab. Due to the short duration of follow-up is not possible to evaluate disability progression, however, no difference was observed between the groups.

CoI: multiple

4 comments:

  1. "It means that whatever is causing MS does not go away; it is still in the brain of MSers. By keeping out auto-aggressive cells with natalizumab you prevent them finding and attacking their target. By removing natalizumab you allow these immune cells to traffic back in the central nervous system find what they are programmed to find and attack."

    Prof G,

    This makes it sound so simply, so why can't the researchers find the target? I'm guessing EAE can't replicate the target, as unknown.

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    Replies
    1. Re: "This makes it sound so simply, so why can't the researchers find the target? I'm guessing EAE can't replicate the target, as unknown."

      To tackle this problem we would need to study the brains of people with MS on natalizumab to see if in the absence of an inflammatory response the cause of MS declares itself. I am thinking virus. Once the immune response is there it seeks and destroys the target and it is difficult to find.

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    2. Prof G,

      I think the observation regarding MS rebound after tysabri is one of the most important to date. It shows that there are probably two processes at work - something activated in the brain (?virus) and then an imune response. We've regarded the immune response as the bad guy, but perhaps it's just doing its job (with collateral damage). I'm guessing if the virus can be controoled then we won't see the immune response (which is bad news for the dmt manufacturers). Perhaps as you have been saying, anti B cell therapies and alemtuzumab are targetting both sides of the problem (cause and response). I also hope the Charcot project will throw some further light on the issue. Good luck.

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  2. Prof G,

    My question - is the target of the immune attack (possibly a virus) actually doing any damage before the immune system wades in? I still don't understand what is damaging the myelin, myelin making cells and the axons i.e. Is the virus causing damage before the immune system gets involved? A lot of MS prizes are awarded to those studying the underlying pathology, but they don't seem to be able to answer the most basic question!

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