Friday, 19 October 2012

Risk factors for Autoimunity with Lemtrada

Whilst looking for what the second generation Lemtrada, which I think may be abit of media spin, I had a quick look at trials and the patents Genzyme and Sanofi have filed.

One of the major side-effects of Alemtuzumab treatment is the development of thyroid disease, where they developed antibodies against the thyrotropin receptor and this cause carbimazole-responsive autoimmune hyperthyroidism. (An overactive thyroid) This occurred in about a third of MSers (Coles AJ et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet. 1999;354:1691.
 
 In addition there were other secondary autoimmune conditions in smaller numbers. This autoimmunity typically arises during reconstitution of the lymphocyte repertoire.

The A's from Cambridge did a study and suggested that individuals with high baseline circulating levels of interleukin 21 (IL-21) were at a higher risk of developing autoimmunity following treatment with alemtuzumab. Jones JL et al. Interleukin-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009119:2052-61.

The Guys from Genzyme think there is something else that increases risk of developing thyroid autoimmunity and this is pre-existing antibodies to thyroid peroxidase.

Margolin D METHOD OF IDENTIFYING RISK FOR THYROID DISORDER. W02008103292.
A method for identifying a patient that is at risk for developing a thyroid disorder that occurs subsequent to treatment with a regimen that depletes lymphocytes, comprising determining whether antibodies directed against thyroid peroxidase or thyroid microsomes are present in the patient, wherein if the antibodies are present in the patient then the patient is at increased risk for developing a thyroid disorder. A particular embodiment is a method for identifying a patient with multiple sclerosis that is at risk for developing a thyroid disorder that occurs subsequent to treatment with a regimen that depletes CD52-positive cells, comprising determining whether antibodies directed against thyroid peroxidase or thyroid microsomes are present in the patient, wherein if the antibodies are present in the patient then the patient is at risk for developing the thyroid disorder.

Of the MSers that did not have baseline thyroid peroxidase antibodies 19% (n=35/182) went on to develop thyroid disease and 25% had thyroid stimulating hormone receptor antibodies, in contrast of those positive at baseline, 50% developed thyroid disease (n=8/16) and 65% developed thyroid stimulating hormone receptor antibodies. These could result in thyroid disease.



As is always the case you have to treat patents with a dose of skepticism  because there is no peer-review of the information, so you can claim loads of things. It is really only lawyers that assess the merits and patents and is on legal aspects like novelty and invention and not whether the data is good quality. However the presence of  thyroid peroxidase antibody is known to be a risk factor for the development of thyroid disease, and MSers are no different. Food for thought if you ever get the option to try it. 

Pharma do loads of work that never sees the light of day in the academic literature, but this surfaces in the patent database

1 comment:

  1. Prof G - in your 'early, aggressive' approach to MS would you endorse Alemtuzumab (leaving aside questions of availability for now) in the following circumstances:

    Recent RRMS diagnosis following earlier attack 1 year ago. No actual disability during attacks (mild sensory disturbance with mild optic neuritis - pain only, no visual disturbance). Some very mild residual symptoms, mainly when tired (sensory plus occasional eye pain). No fatigue; no discernable cognitive issues. For all intents and purposes there is nothing 'wrong' with me at present at all - well, apart from the fact I have MS, of course!

    I am not risk averse. Equally, however, I don't want my fear of what one day might happen to cause me to take unecessary or disproportionate risks - I want to stay alive and well! I've also read something that says there is a theory that really aggressive treatment could be counter productive in people whose MS is mild as it could intefere with the remyelination process? I also saw the post the other day (and noted it is not intended to be used to guide treatments) which reinforced a trend that MS, due to better diagnosis, is becoming a milder disease, population wide, and showed a mean EDSS of just 3.5 after 20 years disease duration and note that, currently, I'm probably in the lowest 10th centile of severity. On the other hand, I realise that MS is not predictable enough that I can be very confident of remaining on that centile and have seen many examples of people's lives ruined by the condition...

    I will definitely seek treatment, it's just a question of which one, and I wondered if you could give me a steer on how you would approach the above? I know this blog isn't for individual consultations/treatment discussions but I guess it is more about the wider question of how one should interpret your belief that early, aggressive is the best option. Does that apply across the spectrum of disease severity?

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