As of April 2013, there are 347 pwMS with documented cases of PML, and 76 have died from this brain infection linked to the JC virus and Tysabri use.

http://chefarztfrau.de/?page_id=716

But there have been more Tysabri deaths documented, linked to antibody reactions, lethal relapses after withdrawal, and cancer.  These are not included in the PML numbers.

The risk of PML is estimated at 11 per 1,000 patients

http://www.fda.gov/drugs/drugsafety/ucm288186.htm

Patients are now tested for the JC virus before beginning therapy.  But many do not realize that just because you are JC- does not mean you will remain that way.  It is possible to become JC+ after beginning treatment.

Illustrating the need for follow-up testing, Bloomgren and colleagues noted the case of one patient whose initial blood sample was negative for JC virus antibodies. Another sample taken 13 months later was positive and the patient developed PML a few weeks later.

http://www.medpagetoday.com/clinical-context/MultipleSclerosis/32743

I've been reading about this online, as people who believed they were JC-, are now testing JC+ and are having to terminate Tysabri infusions.  They are experiencing a rebound of the immune system and ending up worse off than they were before.

A lethal MS relapse after Tysabri withdrawal

http://www.ncbi.nlm.nih.gov/pubmed/23100404

more on the Tysabri rebound effect--

http://ms.about.com/od/treatments/a/The-Tysabri-Rebound-Effect.htm

Another problem is that PML looks like an MS relapse.  It is very hard to tell the difference until a biopsy is taken after death.  (Natalizumab is the drug name for Tysabri.)

The patient developed subacute onset of bilateral blindness following his 44th dose of natalizumab. Ophthalmologic examination was normal, the brain magnetic resonance imaging was not suggestive of PML, and cerebrospinal fluid analysis did not reveal the presence of JCV DNA. The patient was subsequently treated for a presumed multiple sclerosis relapse with high-dose corticosteroids. Two weeks after his 45th dose of natalizumab, he developed hemiplegia that evolved into quadriparesis. Repeated magnetic resonance imaging and cerebrospinal fluid studies were diagnostic for PML. Postmortem histopathological analysis demonstrated PML-associated white matter and cortical demyelination. 

http://www.ncbi.nlm.nih.gov/pubmed/23338729

Diagnosis of PML can be confounded in patients with multiple sclerosis (MS) if new demyelinating lesions develop, and the sensitivity of existing diagnostic tests is less than ideal. In the case presented here, four samples of cerebrospinal fluid were negative for JC virus DNA by polymerase chain reaction, yet brain biopsy eventually proved positive by immunohistochemistry.

http://www.ncbi.nlm.nih.gov/pubmed/23252596  

Please know that I am not a doctor.  I am simply the wife of a man with MS.  Whatever I write here can and should be discussed with your doctors.  I put the following information together for my husband last year, after his neurologist suggested he try Tysabri, even though his MS has been stable for 6 years.  She no longer recommends Tysabri for him, and has told him to "keep doing what you're doing."   If Tysabri is working for you and you love it, this note is not for you. It's for the thousands of newly diagnosed and those who have other options.  All of the following is true, from actual interviews with the doctors who first trialed Tysabri.  Print it out, print out the press releases and studies, talk over all your options with your doctors.  

Everything in the note is sourced.  Click on the blue letters that say "link" to go to articles, research and other sources.  

And be well.

+++++++++++++++++++++++++++++++++++++

June 2012

It's important to go back in time and note that one of the creators of Tysabri, Dr. Lawrence Steinman, realized the potential dangers of this treatment and warned the FDA not to approve it.

From a press release in 2006--Stanford Doctors Spotlight Fatal Flaw in MS Drug Trial

Steinman was involved early on in the development of the drug, publishing on its effects in 1992. Even then, he had suspicions that the drug’s mechanism of action — blocking the entry of immune cells into the nervous system — might also make patients more vulnerable to infections. Indeed, PML is an infection that usually affects people whose immune systems are compromised.

“It was a shocking development that a drug that had so much promise and so many potential benefits ended up causing two deaths and one very serious injury,” said Steinman. “It is kind of a cruel Greek drama, something that may be more beneficial than anything yet developed for multiple sclerosis, but yet may be far more dangerous than those other approved drugs.”

In fact, the inventor and co-author warned about Tysabri returning to the market in 2006.  They questioned the wisdom of the FDA's approval of this drug.

But Steinman and Langer-Gould expressed reservations about the drug returning to the market. They noted that its effects, while impressive, are in general not much better than what is seen with other available drugs: The risk of relapse dropped from an average of two relapses every three years using other approved multiple sclerosis drugs to one every three years with Tysabri.

“Do you want to expose someone to the risk of death for eliminating one relapse every three years?” said Steinman. “I say no.”

“I’m not sure if it is wise to re-approve it,” added Langer-Gould. “The question is, will the FDA rise to the occasion and admit their mistake and try to prevent future mistakes or are they going to ignore it?”

link to press release

Here is an interview with Stanford neurologist Annette Langer-Gould,  co-author of the Lancet paper on Tysabri, about why she spoke up after her patient developed PML in a clinical trial---the title is "So Not Worth It."

Profoundly affected by her experience with this patient, Langer-Gould, a Stanford clinical instructor, now advocates testing new drugs only on people who have exhausted their other treatment options and who have indications that their disease is progressing.

So in March, when an FDA advisory committee recommended that the drug be returned to the market, she took action. She approached multiple sclerosis specialist Lawrence Steinman, MD, a Stanford neurology professor, about writing an article arguing that if a drug has a known risk of death, it should be given only to those patients who are likely to suffer severe disability from their disease. That is almost the reverse of what happened in the Tysabri trials, which excluded the most severely affected patients.

Her biggest concern is that some patients who want to take drugs such as Tysabri might be acting on unrealistic fears about their prognosis and are poorly informed about the drug’s dangers.

(note: drugs are tested on less disabled RRMS patients, rather than more progressive patients,  because pharma knows these patients have natural remissions, and this favorably effects the drugs' results.  This is the "natural course of the disease" argument used against positive results for venoplasty for CCSVI--yet not against drugs.)

link

Sadly, history has shown us, the FDA ignored these warnings about Tysabri.  As a matter of fact, they approved Tysabri by a vote of 12-0.  At the time, it was said that Tysabri "waltzed through FDA approval."  The independence of the FDA panel was called into question by the legal team of one of the patients who died.

  link

According to a New York Times article in March 2005-

Dr. Steinman said he had expressed his apprehensions about the drug in speeches and in an article in the journal Science in July and had been asked by Biogen executives to tone down criticism of the drug.

link

And just this January, the FDA granted a label modification with a more specific warning for Tysabri, so that it can continue to be sold- making Tysabri a "blockbuster" drug.

The Food and Drug Administration approved the revision that would help doctors identify patients with the highest and lowest risks of developing deadly brain infections linked to the drug, the agency said today in a statement.

The label change may push Tysabri’s global sales to $2.5 billion to $3 billion by 2016, Michael Yee, an analyst at RBC Capital Markets in San Francisco, said in an interview yesterday. Without the modification, sales may have reached $1.5 billion to $2 billion that year, Yee said. Biogen, based in Weston, Massachusetts, and Dublin-based Elan split the drug’s revenue.

link to Forbes article

And deaths and injury from central nervous system PML, herpes encephalitis, CNS lymphoma, metastic melanoma, cryptococcal meningitis and other assaults on unwitting PwMS continue daily.  It is not enough to know your JC virus status.  We are only at the tip of the iceberg understanding the long-term implications of this drug.  Most of these neurologic infections do not show up until after two years of therapy.

link to Tysabri and herpes encephalitis

link to Tysabri and Melanoma

link to Tysabri and meningitis

link to Tysabri and CNS Lymphoma

At Jeff's yearly neurologist appointment (which he needs to continue his copaxone treatment), his doctor again tried to talk him into beginning Tysabri infusions.  Even though Jeff has no active inflammation, no new lesions, no new MS progression, and has only healing since venoplasty three years ago, with normal gray matter on MRI---his neurologist utilized scare tactics to make him doubtful about his future.

 "You are a man, you are bound to progress faster.  It's simply the facts.  Tysabri is the best medication we have.  You should start it now to prevent future damage"

Jeff said, thanks, but no thanks.

In light of this sales pitch, the continuing and growing numbers of those with PML (242 with the disease, 52 deaths as of May), and Marie's post on the neurological activation of the herpes virus in the brain of someone on Tysabri---I think we need to go back and document the history of this drug.  I suggested to Jeff that he print out Steinman and Langer-Gould's warning and bring it to his neuro next year.  I hope this information might help some of our readers.  Please share it with your friends and caution them.  

Because the inventor of Tysabri thinks it might be too risky for you to take it.  He would know.

Joan