I don't think we have an answer to that question yet Rex, but the following is an interesting current abstract from Archives of Neurology, October 2006:

Vol. 63 No. 10, October 2006
Arch Neurol. 2006;63:1383-1387.


Background Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an 41 integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection.

Objective: To test the effect of natalizumab treatment on the CD4+/CD8+ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.

Design Prospective longitudinal study.

Setting Academic and private multiple sclerosis centers.

Patients Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus–infected patients.

Main Outcome Measures CD4+ and CD8+ T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound 4 integrin on peripheral blood CD4+ and CD8+ T cells was analyzed before and after natalizumab therapy.

Results: Natalizumab therapy decreased the CSF CD4+/CD8+ ratio of patients with MS to levels similar to those of human immunodeficiency virus–infected patients. CD4+/CD8+ ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4+/CD8+ ratios normalized. The expression of unbound 4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4+ vs CD8+ T cells.

Conclusions Natalizumab treatment alters the CSF CD4+/CD8+ ratio. Lower expression of unbound 4 integrin on CD4+ T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.

http://tinyurl.com/fel85

Cherie,

Results: Natalizumab therapy decreased the CSF CD4+/CD8+ ratio of patients with MS to levels similar to those of human immunodeficiency virus–infected patients.

Hmmm....not exactly what a MS patient needs!! If nothing else the PML and Tysabri association has accelerated research into this previously unknown area.

Harry

Strange, though...that Tysabri alone doesn't seem to cause PML, judging by the thousands of patients/infusions in monotherapy. The Crohn's case is rife with speculation and questionable assumptions, but based upon the huge number of safe infusions, I couldn't say that, on its own, Tysabri will "give" anyone PML. Perhaps if enough ill-advised practices are followed, PML will occur, but there seems to be little evidence (if any) that Tysabri is unsafe as a monotherapy, and I doubt the Elan/Biogen execs are gnashing their teeth and waiting for PML to resurface. A lot of good scientists signed-off on Tysabri this go-around.

JMO...

That's the problem...nobody knows what Tysabri will or won't do in the long run. Given that many MS patients have had some kind of immune altering/modulating medication in the past, using Tysabri as well appears to increase the risk of immune system complications.

This information is not new and the inventors of the drug have cautioned this problem from the beginning. Initially Tysabri was supposed to be used for new and mild cases of MS. Now it is being recommended for those patients who have not responded to the CRAB's .....the very people that would possibly be at greater risk of PML because of already using immune altering/modulating drugs.

As long as the docs monitor their Tysabri patients closely, then they hopefully will be able to avoid serious problems should PML surface.

Harry

There used to be an article on the NMSS website (can't find it at the moment) that defined their involvement in the development of Tysabri, in conjunction with Dr Larry Steinman. Dr Steinman predicted that Tysabri would run into problems many years ago, and reiterated this several times (to medical authorities) before it's release.

The following is one article I've read, in regards to his opinion:


Mar9, 2005

The news last week that the federal Food and Drug Administration was pulling the multiple sclerosis drug Tysabri from the market stunned many in the medical profession, but neurology professor Larry Steinman, MD, who developed the drug, wasn't among them.

....

Steinman said he predicted early in the drug's development that patients might suffer immunological side effects from Tysabri, which works by preventing lymphocytes, white blood cells of the immune system, from entering the brain and damaging the sheath that protects nerve cells. As the nerve cells misfire, patients suffer progressive loss of motor control and ultimately, paralysis.

Steinman and collaborators at Athena Neuroscience (later bought by Elan, the maker of the drug) had first described this novel approach in a 1992 paper in the journal Nature. They soon learned, however, that the drug was not as specific as they had hoped; it not only prevented migration of lymphocytes to the brain, but to other organs as well, such as the gut and the pancreas. With an immobilized immune system, the body would be unable to fight off disease, Steinman said.

"I was right there at the beginning, and I had a worry then because we learned that the molecule we were targeting was not a unique zip code to gain entry to the brain," said Steinman, who heads the doctoral program in immunology.

He said his biggest concern was that patients would become vulnerable to opportunistic infections. Indeed, PML is an opportunistic infection that most often affects AIDS patients, whose immune systems are compromised.

....

Steinman said he was thrilled with the trial results and began to question his own predictive powers regarding the drug's potential side effects. Nonetheless, he continued to voice his concerns at medical meetings and in scientific journals.

In June 2004 review article in Science magazine, he wrote that this approach to treatment carried "at least a theoretical concern that recipients of the therapy would become generally compromised in their ability to fight infection."

Still, the FDA was so impressed with the trial results that it approved the drug in November 2004 under an accelerated process. Analysts predicted the drug—the first new drug for M.S. in eight years—would have a $2 billion market within two years.

At the time of the drug's approval, it had only been tested in a few thousand patients, Steinman noted.

"I worried that when it becomes the blockbuster everyone expected, what would happen when we had 50,000 patient-years of experience?" he asked. "And sure enough, after only a few thousand patient-years of experience, the drug gets pulled because it causes two people to develop a horrendous disease, and one is already dead."

http://news-service.stanford.edu/new...an-030905.html

http://news-service.stanford.edu/new...is-030806.html

Cherie

I think that everyone would be well advised to to take a wait and see approach to Tysabri. I applaud the pioneers, who are on Tysabri now and pray that the long term effects are not detrimental to their health.

Let us all stay informed and proactive with our health concerns and the Drugs that Big Pharma pushes our Docs to push us PwMS to take. Let's not be to quick to jump on the band wagon, untill we're sure it's safe.

There are risks with all Meds, and we must weigh the risks against the benefits and act accordingly. What is best for us, is our first priority.

Hugs,

Not stated is the fact that Steinman had founded two companies (Neurocrine Bioscience in San Diego and Bayhill Therapeutics in Palo Alto), for which he secured millions of dollars of investor capital. Both companies are working on competitive MS drugs.

Amen......

Same thing with Crestor and Coreg - both of which I take. There is no long-term data because they're new. Still, we actually DO know what Tysabri, Crestor and Coreg will do - they will all improve the lives of those who take them.

There are now 4,500 patients enrolled in TOUCH, and 1,700 have received at least one infusion. As we get into calendar year 2007, the perceived odds of contracting PML (based upon the 3 deaths which occurred before the combo-effect was identified) will have dropped significantly.

IMO, patients should be allowed to evaluate the risks themselves. Those who, for whatever reason, would like to see Tysabri fail will predictably capitalize upon the "uncertainty" angle. Those with a real choice to make will look at tangible evidence, and they'll evaluate their own status with regard to the risk of an alternative (and less effective) treatment. Then they will make a choice, with only their own circumstances in mind...and that, IMO, is how it should be.

A lot of people thought going to the moon was too dangerous. Others determined that the risks were manageable and that they could be overcome. Three guys died early on in the program, and as with Tysabri, the program was stopped while NASA determined what measures needed to be instituted, in order to make the capsule safe. NASA then resumed the program - and the rest is history.

And then a whole shipload were lost and that's the history.

But on Tysabri, I do agree that the PwMS should be the one to make the decision after being given ALL the risks and not just the hype.