Review of PML and Tysabri
 

Scary that the MR imaging of PML is indistinguishable from MS and that PML deficits could be permanent and could alter our immune systems irretrievably (wonder what that means for a person's future MS course?) Also that, while early intervention with treatments might help you to survive PML, the damage left could be permanent. Scary too that length of time on Tysabri might be a risk factor in development of PML.

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_DocSum

Neurologist. 2006 Nov;12(6):293-298.

Review of Progressive Multifocal Leukoencephalopathy and Natalizumab.

Aksamit AJ.
From the Mayo Clinic College of Medicine, Department of Neurology, Rochester, Minnesota.

BACKGROUND:: Progressive multifocal leukoencephalopathy (PML), a destructive demyelinating infection which lytically infects oligodendrocytes, has occurred in patients treated with natalizumab. Magnetic resonance imaging (MRI) scan imaging of the brain gives clues to diagnosis but is nonspecific in distinguishing multiple sclerosis from PML. Spinal fluid detection of JC virus is specific but incompletely sensitive. Associated immunosuppression is typically of the cell-mediated type but can be poorly defined on clinical grounds.

REVIEW SUMMARY:: It is apparent that natalizumab is a predisposing factor for developing PML from the 3 cases of natalizumab-treated patients. There is no reliable presymptomatic way to detect PML or JC virus infection of the brain by virologic or imaging surveillance techniques. One patient with multiple sclerosis and natalizumab treatment has survived, indicating that withdrawal of antibody, possibly in combination with antiviral therapy, may permit survival. However, immune reconstitution disease is a risk after immune restoration and withdrawal of natalizumab. PML deficits would be expected to be permanent. The estimate of incidence of PML in natalizumab-treated patients is 1 per 1000. The duration of natalizumab treatment may be an independent risk factor for development of PML.

CONCLUSION:: PML, a usually fatal neurologic infection, should be considered as a risk factor when using natalizumab. The treatment of multiple sclerosis patients with natalizumab is a matter of informed risk, individualized for each multiple sclerosis patient.

PMID: 17122725 [PubMed - as supplied by publisher]

Thanks for posting this, Pantos. I don't know how everyone else feels, but, for me, the possible benefits of Tysabri, do NOT out weigh the risks of PML.:eek:

I realize that it's a personal decision, but I still worry about those who have chosen to take Tysabri. If PwMS hadn't begged for it to be returned to market, I don't think it would have been.

I pray for all of you on Tysabri, to have the best symptom relief you can get with no bad side effects.

Sally,

Those who know me from various MS Forums know of my high doubts about the efficacy of Tysabri. After initially being excited about this new drug back in the summer of 2003, that feeling quickly disappeared as I followed Biogen's introduction of it and started to learn more and more about its dangers.

I too feel that its benefits don't outweigh the risks but at the same time respect anyone's decision to use it...IF they are told about ALL the pros AND cons about the drug. Tysabri is a monoclonal antibody that tampers with the immune system....and that can spell "trouble" in the long run.

I sure hope the many that choose to use it don't run into these possible problems. The Mayo Clinic didn't post this information for nothing!

Harry

None of the three PML cases occurred in patients taking Tysabri in monotherapy, other than the one patient who had been on immunosupressants for a protracted period of time. Although some argue that the immunosuppressed patient had been off those drugs for months, there is no proof that his immune system was functioning normally at the time of his Tysabri infusions.

Every day, the 1:1000 figure becomes more outdated, as thousands of new patients begin Tysabri infusions. I would guess that, should the trend of PML-free therapy continue for a year, many more people will begin to believe in the safety of Tysabri.

I'm afraid I will have to respectfully disagree with you on the Crohn's patient who was indeed on a monotherapy with Tysabri. He had stopped using Infliximab 20 months earlier and hadn't used Azathioprine for 8 months. He was in generally good health (other than from the typical symptoms from Crohn's which he endured for 28 years) and went fishing and hunting.

The JC virus only appeared in his blood during his monotherapy Tysabri use between Feb-June 2003. In one NEJM article, the reps from Biogen/Elan state they asked the physicians who controlled the trial to review his case while in their own article, the physicians say they informed Biogen/Elan first, after knowing about the 2 MS patients who contracted PML!

The family of the Chron's patient was never originally informed about the cause of his death although the Biogen/Elan and the docs knew and stated such in the NEJM article. The family was informed by their doc in April 2005 and then told about the PML cases. The family ran up against roadblocks from the trial docs and Biogen/Elan when they asked to review the all the medical files. When they finally succeeded in being able to do so they were told "try not to make a big fuss about this"!!

This is another reason why I don't think we are being told everything by Biogen/Elan and the docs when it comes to Tysabri and PML. Biogen/Elan have been hanging their hat on the fact that PML did not occur in any monotherapy with Tysabri. The Crohn's patient situation looks like this isn't likely the case.

Harry

When Money is the motivation, it's difficult to believe anything that is said. The slanted trials, the reporting of questionable end results of those trials and the positive words drooling from the mouths of big Pharma.:rolleyes:

The FDA should be protecting the people from this sort of salesmanship and find the truth for us, instead of going along to get along with Big Pharma.

The people are now informed of the dangers from Tsabri, although, I am sure, not fully informed. We are only seeing, as always, what they want us to see.

Sometimes I feel like we are lambs being led to a slaughter.:(

Hey Harry,

As you know, I've been a little freaked out at the number of patients who started and stopped Tysabri on its first approval and are now showing severe allergic reactions to it once they start the infusions again. Despite the warning to discontinue its use at that point -- listed in Tysabri's own prescribing info -- they're setting up those reactive patients to receive Benadryl infusions in conjunction with Tysabri to counteract future allergic reactions. Mind boggling...

Also on the Tysabri site they point out that starting, stopping, and starting it again may produce this type of hypersensitivity with monoclonal antibodies.


"The long-term immunogenicity of TYSABRI® and the effects of low to moderate levels of antibody to natalizumab are unknown. Experience with other monoclonal antibodies suggests that patients who receive therapeutic antibodies after an extended period without treatment may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled treatment. It is not known if this will occur with TYSABRI (see WARNINGS, Hypersensitivity and ADVERSE REACTIONS, Infusion-related Reactions)."


This thread's discussion about the Crohn's patient reminded me of something else about his case that was documented in the NEJM article, so I pulled out my copy (I have dozens of Tysabri articles printed up and filed here). The Crohn's patient who came down with PML had also stopped Tysabri for several months and resumed the treatment later.

No JC virus appeared during any of his other drug treatments which, like Harry said, had ended months before the JC virus was finally noted in his system. No JC virus appeared during his first 3 Tysabri infusions or during the 9 months he was on placebo.

But...the JC virus showed up immediately after his Tysabri infusions resumed and the viral load increased substantially during the 5 infusions before he was admitted to the hospital. It's always bothered me that the Crohn's patient came down with PML after fewer infusions than the other patients, especially since he had been on placebo for much of the trial.

It was reassuring to think that Tysabri must be pretty safe for at least a couple of years, but now I think I'm even more freaked out. What if there's something else going on entirely? They just don't understand these drugs yet. :(

P.S. Many of us already knew that there is no test for PML, no treatment, and that its damage is permanent. I just don't think that fact has been stressed enough to potential patients who haven't followed the whole saga as closely as we have.

Check out the "Patient Medication Guide" and the "Product Information" on the Tysabri website
http://www.tysabri.com/product-information.html

Hi Susan,

Reading your post just re-emphasizes the major concern I've always had with this drug...and that is the way Biogen/Elan rushed its introduction into the marketplace!

Even though they were aware of the dangers of a monoclonal antibody and certainly didn't have any kind of reliable safety data, Biogen/Elan focused solely on the so-called beneficial stats of Tysabri from one year data from 2 of 99 world-wide Phase III trials going on at that time. That's what they used to convince the FDA to accelerate the approval of the drug while at the same time making several press releases on how wonderful this drug was going to be for all MS patients. The problems that were happening were swept under the carpet and got little if any attention.

I really hope that MS patients don't pay the price for this kind of drug marketing.

Harry

Don't forget the gushingly negative comments of competing Big Pharmas.

IMO, the efficacy and safety of Tysabri is no less than its competitors, and its potential to provide relief is far greater. I think the number of patients already enrolled is a testament to their confidence.

:rolleyes:


Have you noticed that the talking heads who were so visible prior to Tysabri's re-approval have disappeared? Maybe, once there was no chance of queering the re-approval, the hired guns lost interest in the "safety profile" of Tysabri? You seem to be the last guy carrying the banner.

I think the number of patients already enrolled is more of a testament to the inadequacy of the CRAB meds. The CRABs are almost universally hated -- even by those who believe they're getting a modest benefit from them and find the side effects tolerable.

I'm guessing the reason some of them aren't around anymore is because there isn't too much say about whether Tysabri is going to get re-approved. I stated from the very beginning, after the drug was originally pulled, that the FDA would re-approve the drug because there is simply too much money at issue here.

Exactly the same thing happened over on the ThisIsMs forum after Tysabri got its original approval...only in the opposite way. A few other people and I continually stated at that time that Tysabri was a potentially dangerous drug and that a great deal of caution had to be followed when using it. I can't count the number of times some readers called us "Tysabri bashers, fear mongers and hidden agenda people over the course of about 4 months. And then, out of the blue, Biogen pulled the drug after PML showed up. All of a sudden these people disappeared and the name calling stopped...wonder why?:)

And I somehow doubt that we have heard the end of the problems with Tysabri. This drug plays with the immune system too much and there is simply too much unknown about it at this time.


Won't disagree with you on that one...but in the Big Pharma business, these competitors are ruthless when it comes to bashing one another. Not surprising when billions of dollars are on the line!!!

Afraid I can't agree with you on the safety of Tysabri at this time....even Biogen admits they don't know any long term effects on the drug. As for the efficacy, it really doesn't take much to beat the record of the CRABs, does it?

Harry

We are lambs being led to the slaughter. It's not just PWMS, though. It's any disease that's medically poorly understood. As a society we've become so conditioned to the idea that drugs will eventually fix, or at least help, any medical condition that we often submit to drugs that are as poorly understood as the disease we may have. Many times, belief in drug intervention is completely justified. In the 20th century medical understanding proceeded at warp speed. But medicine is not an exact science, a fact that many people find difficult to accept. In particular, medical understanding of the CNS, brain chemistry, human psychology, and the things that can go wrong with them are not yet ready for prime time.

I have PPMS. My neuroligist and I know this because for thirteen years I never had a relapse, but only steady progression that got faster as the years passed, and never remitted or slowed down. What you might call a textbook case of PP. During the last two years, I've had several episodes that seem to be relapses, causing my neurologist to think that my PP may now be relapsing progressive. My MRI doesn't enhance, indicating that there is no active inflammation involved. My point in talking about all of this is to explain why I have resisted all of the current drug interventions for MS. In my particular case, none of the drugs make any rational sense. And "you never know" doesn't work for me as a reason for taking heavy hitting drugs, particularly when their long term consequences are lethal or unknown. Because of this I have a jaundiced, not to say cynically skeptical, view of the efficacy of current MS drug treatments.

And there have been times when I have been accused by other PWMS of "losing hope." Since I never expected medical science to come riding to my rescue, I never quite understood which hope I supposedly lost. I follow every new drug intervention that comes along, looking at each one with my own personal MS profile in mind. None of them has held up for me, although several years ago I allowed myself to be talked into trying a course of cytoxan. It did nothing for me. Nor did the solumedrol given in tandem with the cytoxan.

I think that any drug intervention is a personal decision made by a PWMS. Not only is MS poorly understood medically, but it's highly individual. My neuroligist calls me "the other doctor," and that's the way it should be. PWMS need to be especially proactive, researching their own drug options and not accepting drug treatment until they understand the pros and the cons. Neurologists are children of society every bit as much as we are; being doctors, they want to fix illness and are members of the drug culture. People accepting heavy hitting drugs need to be as secure as possible in their own minds that they're making the right choice.

Chris

Well said. Chris. Thank you.:)

KingRex, are you on Tysabri or going on Tysabri? I'm sorry, if I missed your MS story somewhere, but just wanted to ask...Thanks.:)

I appreciate your vigilance, Harry. Somebody's got to do it.:D Some of us PwMS are not as proactive as we need to be and we need people like you to remind us, even if we don't want to hear it.

The "talking heads" I was referring to are not the denizens of these boards; they are the "experts" trotted out by Teva and the other drug companies whose drug sales stood to suffer if Tysabri was approved.; all those doctors on their payrolls, via lucrative "research grants", who carried on so, as well as the columnists who seemed to consistently "get it wrong". Why are they all silent now? If this was really about safety, why would they stop talking?

IMO, it was all about money...you're right. You just have the identity of the bad guys wrong.

Don't I know you from somewhere?

Rex,


These "paid experts" by Teva, Serona and Burlex are no different than those from Biogen/Elan. Before Tysabri even got into general use the first time around, Biogen sponsored a web cast in Philadelphia which featured a host (he could have worked "Let's Make a Deal" with his antics) and a panel of "experts" in front of an audience of specially invited medical guests.

Talk about watching a circus of promotion by Biogen...big time marketing at its best!! All of these big pharmas have marketing/sales departments which spend millions on promoting their drugs to the docs and public. But don't for one minute think that Biogen's competitors have gone away. All of these people lurk in the background, waiting for the one event or incident that they can pounce on order to make the "other guy" look bad and perhaps get back a percent or two of that lucrative MS medication market....those 2% can translate into $ millions!! And with Tysabri, it isn't "if" something will happen, it's "when" something will happen.

Biogen/Elan are no different than the other people in this area...they just happen to have the latest MS drug out there. When these other pharmas come out with something else, the shoe will be on the other foot and Biogen will be doing exactly the same thing as these other guys are doing now. It has nothing to do with interest in MS patients but everything to do, like you said, about the money!!

Harry

Your name looks familar. Were you at PT? I may remember you from there, although I have holes in my head.:D

Not what I meant.



Riiiight...as I said, you seem familiar. Maybe MSWorld?

I don't get it:confused: I don't know you and I simply asked you a question. Although, I do go to MSW on occasion, I don't remember you from there.

If you are infamous there for not answering questions, then I understand. Forget I asked.:cool:

OK, I have read all the negative on why we, as a MS sufferers,should not do Ty. From greed to 3/3000 dying and everything inbetween.

I ask simply: if there is a slight chance of at least staying the same, never mind improving, don't we take that chance?

Living with MS stinks. Any chance,that makes sense chemically, in my eyes is worth the risk. People die from car accidents among many other things in greater number than 3 out of 3000. Get real and look at the stats. Asprin or drowning in a bathtub is more risky. Everything we do is risk. Limiting risk is prudent. I would not have taken Ty if the risk outweighed the benefit. I want my life back! For that, I will take those odds.

Pete

Hi Pete, and welcome to the board.

This is a situation of "to each, their own". Some people would be willing to take that risk, others wouldn't.

I am on a non-mainstream medication for MS, and have faired wonderfully on it. Although FDA approved, it was not intended for MS (like many of the drugs we take). This is a very mild and cheap drug, oral, proven safe over 40 yrs, with only minor short-term side effects.

This drug has taken me from constant unrelenting pain, numb hands, claw hand, barely able to walk, back-to-back attacks, an ever-increasing EDSS . . . to a VAST improvement in ALL facets of this disease. No, it's not scientifically proven to kill 3/3000, but according to anecdotal evidence, it IS working for a lot of people.

I have wondered why people wouldn't be willing to try it too . . . :confused:

In fact, I remember one time someone saying on one of the boards "I would give my arms to have some assemblence of life back". I said "why not try this drug then . . . better then losing your arms, I reckon?". :confused: She didn't even answer me. :cool:

What I am trying to say is that people have their reasons for not trying the various drug options. Personally, I haven't even tried the CRABs, yet I am now probably in better shape then most anyone else I know who has had MS for as long as I have. I was not though, two years ago!

I will use Tysabri, if it proves safe and effective in the LONG run. I will let the risk-takers have a go at it first though (and thankfully there are people out there who are willing to do this for the benefit of all ...)

Cherie

Hi Pete, Welcome to NeuroTalk. :)

I hope Tysabri gives you your life back. I really do!!

I pretty much Ditto what Cherie said. I am also on LDN, for the last 3.5 years.

Please come back and let us know how you are doing on Tysabri....And thank you for your pioneering for us.

I am now registered on this board as well as "this is MS" board. Whatever works. That's all I'm trying to say. We all have to take a risk doing something.
Laying back because somebody said X might happen is for the birds. As you can tell, I'm very proactive. Do something as long as it is not to harmful. The FDA is and has to be VERY conservative. Tysabri did not have to beg to be put back on the market. The #'s spoke and low and behold, it has worked for some. Isin't 1 worth it?

Pete

Biogen indeed did have to "beg" to get Tysabri back on to the market. The FDA held public hearings and invited MS patients to speak at these hearings. That is rarely done. They also pushed up the time frame by 4 months for the appeal process. There was a lot going on in the background with Tysabri and the huge amount of money at issue with its re-approval certainly didn't slow things up.

The biggest problem Tysabri had and still has is the fact that nobody knows the correlation between it and possibility of contracting PML. And when the docs can't tell the FDA, the FDA gets twitchy!

Harry

Harry, give it a break. If getting rid of polio waited to make SURE it was safe, we'd still be with it. As far as money, isin't 1 QoL improvement worth the money? They couldn't approve this(Ty) fast enough. I have read your doubts and you offer nothing more than "Let's see." Live with this, not your wife, but you.

The same thing I would tell politicians about embryonic stem cells. If you are against it, great, but don't use them if they work and you have something go wrong.

Pete

It's just Harry's opinion, Pete. There are good reasons and room, for both of your opinions. I understand your reasonings for the choice you made for yourself.

My choice is to stay on LDN for the time being. I don't think Tysabri is all it's cracked up to be and one of the sides could be PML. Simple as that. In the meantime, my MS isn't going anywhere, and neither is yours.

I hope it works for you and gives you a better QOL. At this point, that's what it's all about. If I were younger and had a more aggressive type of MS, I would , maybe, make the same informed decision you have made.

It's all about the risk vs benefit Pete. While some people will take whatever risk is involved with Tysabri, others will not. This becomes an individual decision.

But please don't compare the polio vaccine back in those days with Tysabri of today. What happened with Tysabri and all of the frustration and problems that we are seeing is the result of Biogen/Elan's rush to capitalize on big time revenue. The medical safeguards of today's science are far superior to what they had back in the 50's but unfortunately they weren't used with Tysabri to the extent they could have been.

I continue to read on other MS sites the severe reactions that some Tysabri users are experiencing. These patients used Tysabri during the first round before the drug was pulled. They apparently produced antibodies to the drug and now when they are trying to go back to using Tysabri, the problems are surfacing. They usually can't ever use the drug again and are frustrated more than ever. A lot of this could have been avoided if Biogen took the time to follow their original plan for the trials. You now have to wonder what else was "skimmed over" and not checked out properly. Taking a risk with your health and medication is one thing....taking a risk without being given the proper information is another and something that MS patients don't need to take on.

Harry

OK, I get it now. I went to MSW and read a few of your posts. Nuff said.:rolleyes:

I do enjoy your posts, Rex.;)

You get what?

You don't have MS and you're a Tysabri/ELN Invester.

Yeah, that's what I'm all about.

Funny though, that you read "a few" of my posts over there and came away with that capsule impression of me, considering that 95% of my posts had nothing to do with Elan. Somehow you were able to hit upon that 5%.

So, what name do you go by on MSWorld, Sally? Just curious. :) As I said, you seem very familiar; I'd like to read some of your posts over there, too.

This wouldn't be the former MikeElan would it?:eek:

Harry

I also read enough to know that you and your expertice has been very helpful and supportive there, as you are here. Don't get your shorts in a wad, you are welcome here.:D

Update:

A new obstacle I have not read about. Would appreciate comments.

Felt good going into Friday's workout. Workout itself went well.

Problem: As I have increased time for workout, my core body temp, something I had given no thought to in years, went up causing MS to reassert itself. The only thing I can come up with is backing off.

Thoughts.

Pete

Now that has the ring of sincerity. ;)

Pete, Exercise is a good thing. The symptoms that show up due to exercise and the increase in body temp is short lived. Once you have relaxed and/or cooled down the symptoms should also calm down.

You can use a fan while working out and one of my favorites...take a cool shower once your done working out. A cool shower will bring you core temp down quite fast and you will smell better:D

For the first time, I can say MS has got the best of me. I can't push harder by increasing more than I'm doing. I have to back off because I raise my core body temp. causing the MS to flare up. Frustrating to say the least. ****** is a better word. If anyone has ideas, glad to here them.

Pete

What snoopy said. Use a fan or A/C when exercising and/or jump in a cool shower after your workout.

Never exercise in the heat or even room temp, as we PwMS tend to over - over heat.:eek: