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  • pinvestment pinvestment Mar 12, 2005 9:09 AM Flag


    I think you are missing the point - human disease does not fit into distinct little categories - it occurs along a continuum - there is almost no disease that is as on/off switch there are many on/off switches - that is why while one person may smoke for 30 years and never exhibit any signs (disease from smoking) a different person that smokes for 30 years and can develop lung cancer, heart disease, bladder cancer, emphysema and a host of other maladies - that is a genetic predisposition - it determines your risk of developing a disease given a certain environemental factor - that is why your statement of a direct causative link is false - if there was a direct causative link then everybody treated with enbrel would have demyelinating disease, die from severe infection and develop lymphoma but those cases have been much lower and other occured in maybe 1 in 500 patients -
    I believe that tysabri + avonex dual treatment may be a risk factor - but it is only one of several and the others include 1. previous immunosuppression( in the near term including chemo and steroids) 2. re-infection with jc virus 3. genetic predisposition (this may be the largest) 4. previous JC infection status 5. concurrent HHV-6 infection 6. JC virus serotype - and also add in that the steroids that patient one got because of the diagnosis of a MS flare up (for two months) instead of PML pretty much sealed her fate - that was a mis-diagnosis and the wrong treatment (those are other risk factors)

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    • Pinvestment, Enjoy reading your posts.

      In the later part of your reply to creedster you list the 6 risk factors for the combo therapy. You say that the genetic factor (variance) is one of the major ones.

      Question is, if genetic variance is the major cause of PML in the combo theraphy then don't you think that he return of Tysabri will be more challenging ? Because Avonex has not been reported to casue PML so far. Therefore TYsabri is by default blamed for this event. But if you say that genetic make-up (variance) may be a major factor responsible for PML by Tysabri then, every patient who wants to take Tysabri has to be "gentically screened" for their "tolarence" to Tysabri. This I think is even a bigger problem. What do you think ?

      • 4 Replies to givvens
      • I think that the genetic risk of developing PML is exposed by the dual avonex + tysabri treatment in concert with the steroids that the patients were receiving during disease progression

        it is the same as someone who has a family history of cancer - if they smoke or work in a uranium enrichment factory they will probably develop cancer - if they don't put themselves at additional risk then they may never develop cancer - the environmental stresses you put on your body are able to expose your genetic weaknesses

      • I think the genetic predisposition becomes a factor in the determination of what happened to those poor 2 PML cases susceptibility due to genetic factors will be tracked and identified, and in the meantime this medicine will be brought back into the marketplace with sufficient warnings and labeling to allow its total and unequivacable distribution to those who need it most,

        and the lawyers and bashers can go fuck themselves.

      • Good question.


      • I think the Sun will come up in the morning.

        The stock market will will be very active this Monday.

        And most unfortunatly the blind bashers will try to cross this freeway of knowledge.

        I'll be looking for your "greasy" spot as I drive by!

    • My personal view is that this stuff is basically best modeled as a multi-state markov chain. (Or if you are a real bear for punishment a semi-markov chain instead). At its simplest, the model has a chain that is linear. Each node as a transition probability to the state on the right and on the left as well as a transition probability to itself and a transition probability to the rightmost stage of PML onset. At the begining of therapy, you are in the left most state. Depending on what therapy you get, you can trannsit to the right or transit yourself or transit to PML. Conditioned on the sort of therapy, the transition probabilities change. In normal folks with no treatment, the transition probability to the absorbing PML state is extremely small. Each state has an increasing probability of transition to PML and increasing probability of transition to the next state on the right as you go from left to right in the chain. Likewise, the transition probability from right to left goes down and the self transition probability goes down. As you increase the agression in your therapy, you skew the transition probabilities to favor the transition to the right and the transition to PML. Avonex by itself and from what we have seen of the limited Tysabri mono trials does not seem to skew the probabilities much. Add other supressive agents and you head off to the right in a bigger hurry. But even with full blown AIDS, you only have a 5% probability of doing the transition to that PML absorbing state. The reason I have a set of non-disease states is to allow for the effects of usage over time. The fact that avonex decreases Tysabri clearance means that the first dosage has a different effect than the nth dosage.

      Most exposure to disease causing agents can be modeled in this manner, be they infectious or otherwise.