ME/CFS Research (Dr Amolak Bansal) and Management (Dr Charles Shepherd)

[Kati]

Interesting (and rather concerning) drug alert from the FDA in relation to viral reactivation in two people who had been taking rituximab for SLE (where approx 10,000 patients have been treated with rituximab):

Information for Healthcare Professionals: Rituximab (marketed as Rituxan)
FDA ALERT [12/2006]: This Alert highlights important emerging safety information about Rituxan. Two patients have died after being treated with Rituxan for systemic lupus erythematosus (SLE). The cause of death was a viral infection of the brain called progressive multifocal leukoencephalopathy (PML) that is caused by reactivated JC virus. Latent JC virus is present in about 80 percent of adults.

Rituxan is a powerful immunosuppressant that eliminates mature circulating B-cells for up to nine months. Rituxan is approved for CD20-positive, B-cell, non-Hodgkins lymphoma and for moderately-to severely-active rheumatoid arthritis when there has been inadequate response to other treatments. Rituxan is being studied for other indications, and is prescribed off-label for other serious diseases and conditions such as SLE. The sponsor estimates that approximately 10,000 patients with SLE have been treated with Rituxan. Reactivation or exacerbation of viral infections including JC virus leading to PML may occur when patients receive Rituxan for any reason. FDA is working with the sponsor to gather additional information about the occurrence of PML in patients treated with Rituxan and to strengthen the Warnings about the risk of PML in the product labeling for Rituxan. Patients who have been treated with Rituxan and present or develop new neurological signs or symptoms should be evaluated for PML.

We know that SLE patients are more prone to take high doses of Prednisone to suppress their disease. It is a powerful immunosupressant. Prednisone given with Rituxan presents an added risk for jc virus reactivation, and death.

In contrast to our patient population, ME very seldom get prescribed Prednisone. So it is a very different ballgame.

 

[charles shepherd]

We know that SLE patients are more prone to take Prednisone to suppress their disease. Prednisone is a powerful immunosupressant. Prednisone given with Rituxan presents an added risk for jc virus reactivation, and death.

In contrast to our patient population, ME very seldom get prescribed Prednisone. So it is a very different ballgame.

You make a perfectly valid point about the way in which use of other immunosuppressive drugs (e.g. steroids) could increase the risk of reactivation of JC virus >>

The Role of Immune-Suppressing Drugs
The JC virus often attacks when a person’s immune system is at its weakest—a weakened immune system can no longer fight off invading viruses. It’s the perfect opportunity for the JC virus to awaken, cross the blood-brain barrier, and begin attacking the brain. People with MS are at an increased risk for PML because their immune system is often compromised as a result of the condition. Further compounding the problem, several medications used to treat the symptoms of MS can compromise the immune system. These medicines include natalizumab (Tysabri), dimethyl fumarate (Tecfidera), and corticosteroids. Prior treatment with immunosuppressant medications, including azathioprine, cyclophosphamide, dimethyl fumarate, methotrexate, mitoxantrone, or mycophenolate mofetil, can also increase the likelihood that a person with MS will develop PML after exposure to the JC virus.

In 2012, the FDA approved the Stratify JCV Antibody ELISA test. One year later, a second-generation test was released to enhance the test’s accuracy. This JC virus–detecting test can determine if a person has been exposed to the virus and if it is present in his or her body. A positive test does not mean a person with MS will develop PML, but only JC virus–positive individuals can develop PML. Even with a negative result, you’re not 100 percent safe — you can be infected with the JC virus at any point during your treatment.According to the FDA, the longer a person takes immune-system suppressing medicines, the more at risk a person is for becoming infected.

However, you could also argue that there is evidence of viral (i.e. EBV) reactivation in ME/CFS, possibly as a result of defects in NK cell function and number, and that this could also be a factor in increasing the risk of reactivation of JCV occurring in ME/CFS

So I would not agree that ME/CFS is a 'very different ballgame'

The simple answer is that in our current state of knowledge, with only very small numbers of people being ME/CFS being treated with rituximab, and no data from long term follow up (i.e. 5 + years after treatment or on treatment) on the reactivation of JCV we just don't have the answers

In practical terms, if it does turn out that there is a risk in ME/CFS, say at the same (extremely low) level as found in this data on SLE, would a 1 in 5000 risk of developing JCV complications justify the use of this drug in people with ME/CFS - on the basis that a significant proportion of people would gain benefit

This is an interesting ethical dilemma that may have to be discussed as time goes on…...

 

[charles shepherd]

You make a perfectly valid point about the way in which use of other immunosuppressive drugs (e.g. steroids) could increase the risk of reactivation of JC virus >>

The Role of Immune-Suppressing Drugs
The JC virus often attacks when a person’s immune system is at its weakest—a weakened immune system can no longer fight off invading viruses. It’s the perfect opportunity for the JC virus to awaken, cross the blood-brain barrier, and begin attacking the brain. People with MS are at an increased risk for PML because their immune system is often compromised as a result of the condition. Further compounding the problem, several medications used to treat the symptoms of MS can compromise the immune system. These medicines include natalizumab (Tysabri), dimethyl fumarate (Tecfidera), and corticosteroids. Prior treatment with immunosuppressant medications, including azathioprine, cyclophosphamide, dimethyl fumarate, methotrexate, mitoxantrone, or mycophenolate mofetil, can also increase the likelihood that a person with MS will develop PML after exposure to the JC virus.

In 2012, the FDA approved the Stratify JCV Antibody ELISA test. One year later, a second-generation test was released to enhance the test’s accuracy. This JC virus–detecting test can determine if a person has been exposed to the virus and if it is present in his or her body. A positive test does not mean a person with MS will develop PML, but only JC virus–positive individuals can develop PML. Even with a negative result, you’re not 100 percent safe — you can be infected with the JC virus at any point during your treatment.According to the FDA, the longer a person takes immune-system suppressing medicines, the more at risk a person is for becoming infected.

However, you could also argue that there is evidence of viral (i.e. EBV) reactivation in ME/CFS, possibly as a result of defects in NK cell function and number, and that this could also be a factor in increasing the risk of reactivation of JCV occurring in ME/CFS

So I would not agree that ME/CFS is a 'very different ballgame'

The simple answer is that in our current state of knowledge, with only very small numbers of people being ME/CFS being treated with rituximab, and no data from long term follow up (i.e. 5 + years after treatment or on treatment) on the reactivation of JCV we just don't have the answers

In practical terms, if it does turn out that there is a risk in ME/CFS, say at the same (extremely low) level as found in this data on SLE, would a 1 in 5000 risk of developing JCV complications justify the use of this drug in people with ME/CFS - on the basis that a significant proportion of people would gain benefit

This is an interesting ethical dilemma that may have to be discussed as time goes on…...

Incidentally, does anyone know if the ME/CFS patients in the Norwegian trials are/have been tested for JCV (antibody ELISA test) before taking part in the trial and whether testing for JCV forms part of the follow up?

 

[BurnA]

1 in 5000 risk of developing JCV complications justify the use of this drug in people with ME/CFS - on the basis that a significant proportion of people would gain benefit

This is an interesting ethical dilemma that may have to be discussed as time goes on…

RTX is also prescribed for RA, are RA patients at an equally elevated risk ?

What % of people suffer serious adverse reactions to vaccines in general ?

 

[Gingergrrl]

@charles shepherd Am confused after reading most of this thread. Do you view the established autoimmune dosing schedule of RTX as safe, and that it has had enough clinical trials, and only that the newer ME/CFS protocol is in question?

If someone has an autoimmune profile with multiple auto-antibodies, positive ANA titer/pattern, and immune system shifted to MCAS/allergic side, and they followed the original autoimmune dosing schedule (two doses total at one week apart) would you feel this has more evidence behind it than the newly developing ME/CFS dosing protocols?

Am unclear why an entire protocol or scheduled trial in the UK would be scrapped based on anecdotes of patients who perhaps did not have specific auto antibodies that they were targeting? (Am saying perhaps b/c I have no idea.)

 

[charles shepherd]

RTX is also prescribed for RA, are RA patients at an equally elevated risk ?

What % of people suffer serious adverse reactions to vaccines in general ?

By strange co-incidence a new study on JCV reactivation in RA has just been published:

http://www.ncbi.nlm.nih.gov/pubmed/27063911\\I

Interesting conclusion following on from the current discussion:

We detected a viral reactivation in PBMCs and serum during the RTX treatment that did not seem to be influenced by either use of immunosuppressive drugs or the length of treatment with the monoclonal antibody. Although this reactivation was asymptomatic, the viral presence in blood could increase the probability of the appearance of a neurotrophic variant of JCV.



This is really Jonathan's area of expertise if he is around...….

NB: Rituximab is a monoclonal antibody that knocks out B cells. It is not a vaccine.

 

[charles shepherd]

@charles shepherd Am confused after reading most of this thread. Do you view the established autoimmune dosing schedule of RTX as safe, and that it has had enough clinical trials, and only that the newer ME/CFS protocol is in question?

If someone has an autoimmune profile with multiple auto-antibodies, positive ANA titer/pattern, and immune system shifted to MCAS/allergic side, and they followed the original autoimmune dosing schedule (two doses total at one week apart) would you feel this has more evidence behind it than the newly developing ME/CFS dosing protocols?

Am unclear why an entire protocol or scheduled trial in the UK would be scrapped based on anecdotes of patients who perhaps did not have specific auto antibodies that they were targeting? (Am saying perhaps b/c I have no idea.)

I think you have misunderstood/misinterpreted what I said in my summary of what Dr Bansal had to report last Saturday

Dr Bansal did not say that the UK trial would be scrapped on the basis of anecdotal patient evidence - which means the patients from UK, Canada and America who have been treated in America but not as part of a clinical trial

As I have tried to explain, the fact that some of these case reports are disappointing, and in some cases causing concern in relation to adverse effects, means that this type of patient evidence does need to be taken into consideration when it comes to how, where and when a UK clinical trial takes place

Dr Bansal made it clear that discussions are on-going (which seems very sensible to me), and that's as far as I can go - I am reporting what happened at a meeting

I am not involved in the rituximab trial here in the UK - but am in contact with people here in the UK who have been treated (without success) in the USA

 

[BurnA]

NB: Rituximab is a monoclonal antibody that knocks out B cells. It is not a vaccine.

Oh i know, sorry i was really replying to your ethical dilemma of 1 in 5000 potentially suffering for the benefit of others and trying to draw a comparison to vaccines in general.

 

[JoanDublin]

Sickness behavior: A perspective promoted by a vet and likely embraced by your neighborhood psych.

I agree. Why not just say 'symptoms'? Behaviour suggests a willful action

 

[Gingergrrl]

@charles shepherd sorry I didn't explain my question well. Was just wondering if you viewed the established autoimmune protocol of RTX differently than the (currently) experimental ME/CFS protocol of RTX?

 

[charles shepherd]

I agree. Why not just say 'symptoms'? Behaviour suggests a willful action

Yes - that would be OK. Problem is that 'sickness behaviour' is fairly firmly embedded as a medical definition for this response to infection

 

[charles shepherd]

@charles shepherd sorry I didn't explain my question well. Was just wondering if you viewed the established autoimmune protocol of RTX differently than the (currently) experimental ME/CFS protocol of RTX?

Sorry - but I'm not sure if I fully understand your question

My understanding is that when it comes to why this drug might be effective in ME/CFS the answer remains uncertain

A number of explanations have been put forward - including an effect on an autoimmune component and removal of latent viral infection (once subjugated, B-lymphocytes also serve as a reservoir for sustained latent infection in EBV).

 

[JoanDublin]

Yes - that would be OK. Problem is that 'sickness behaviour' is fairly firmly embedded as a medical definition for this response to infection

Doesnt mean you cant change it or challenge it...given the psych interpretations of that phrase it beholds you to do so, I would think. Im saying that as a parent of a youngster who was told that his illness 'behaviour' was his 'problem' so I know how it can be interpreted

 

[Gingergrrl]

I just meant that it seemed the ME/CFS protocol was being viewed as experimental or more dangerous and was curious if you felt these same concerns also pertained to the well established autoimmune protocol of RTX which is a different dosing and schedule? Sorry, am not sure how else to phrase it?

 

[charles shepherd]

I just meant that it seemed the ME/CFS protocol was being viewed as experimental or more dangerous and was curious if you felt these same concerns also pertained to the well established autoimmune protocol of RTX which is a different dosing and schedule? Sorry, am not sure how else to phrase it?

Ah - I see what you are getting at

I don't have any personal experience in using rituximab

So all I can say is that the protocol used by the Norwegians appears to be sound and safe what I know from both the published papers and from meeting the docs involved

The protocol for a UK trial has not yet been prepared and it may well have some differences to the ones used in Norway

We will just have to wait and see.......

This is a question where Jonathan is in a far better position to give an informed answer/opinion!

 

[taniaaust1]

If I had more energy, I'd do more activity. Use the research funds on finding out why I don't have enough energy, - not fiddling around the edges making better stretching exercises.

lol well said.

6 UNREFRESHING/POOR QUALITY SLEEP
As already noted, any form of chronic stress, is going to have a direct effect on the quality of sleep and may therefore help to perpetuate any existing sleep problems – non restorative sleep; fragmented sleep, daytime sleeping – that are common in ME/CFS.

I actually do agree with that part. Im experiencing this myself right now as Im actually having nightmares over how the state disability service has treated me re the ME/CFS so keep waking up with anxiety attacks over this ( they deem ME/CFS not a disability which needs any support services). Im suffering both severe and chronic stress from this and it has made a couple of my ME/CFS sleep issues come back or intensify.

This is turn cause Im not not sleeping hardly much at all at night (only 2-3 hrs a night) has now caused daytime sleepiness and me falling asleep and needing to sleep a times during the day.

Seeing stress can make our sleep worst, maybe a good way to treat our sleep issues would be for them to fix the issues around the medical and government discrimination around ME/CFS and start actually educating the professionals, as who sleeps well when they are getting neglect and abuse.

Someone should do a study on how our treatment by the disbelievers is making us worst and not allowing us a chance to even start to recover. Stress certainly does bad things to my immune system and can give me a sore throat.

 

[taniaaust1]

Good points from the interactive session half way through:

INTERACTIVE SESSION: WHAT DO PATIENTS WANT FROM A GOOD HOSPITAL BASED ME/CFS REFERRAL SERVICE?
Moderated by Bill and Janice Kent from ReMEmber


Members of the audience listed all the key components that they want to see included in a hospital based referral service for people with ME/CFS:

1. All patients to be examined by an expert consultant physician
2. Prompt referral and accurate diagnosis
3. A domiciliary service for the severely affected
4. A clinical nurse specialist for the severely affected
5. A specialist occupational therapist
6. A dedicated service for children with ME
7. Recognition from all these practitioners – and GPs – that this is a biomedical condition
8. Compulsory re-training for all healthcare professionals who provide services to ME patients
9. Better access. Some clinics are located upstairs in buildings without lifts, and some have no parking facilities (or inadequate parking)
10. Access to a specialist doctor for more than the 12 months currently offered before being referred back to their GP who is probably not knowledgeable
11. An annual review like that offered by Stoke Mandeville to spinal injury patients… This would allow ME patients to contact their ME unit (e.g. by phone) if they should encounter problems their GP can’t help with.

that's excellent, I dont think Ive ever seen such a good list. thanks to those who got that together.

 

[taniaaust1]

The thing is, with hindsight, just about anyone could identify stresses at any particular point in their life. Final year exams at secondary school; parents divorcing; study at university; demanding job with difficult co-workers; having a baby; having three kids under five and working; spouse with cancer; moving overseas; having your child die; training for the olympics; financial problems; divorce; and so on ....

Most people's lives are a series of challenges. But not everyone gets ME/CFS. So pointing to stress as a cause (as Dr Bansal does repeatedly) is not very helpful. (edited for spelling)

stress for me is exactly what triggered mine into ME/CFS. At first I only got sick with viral symptoms (which I didnt know at time was ME/CFS starting) every time I had an exam I was studying for or a big assessment I was doing. Every time I was hard into the studies and under a deadline, I'd come down with severe viral symptoms eg high fever. I only got sick with stressors alone for the first year (exercise in that year didnt make me sick, that came later when the illness had gone to being there full time and not just developing on stress).

So for some of us it can be the obvious initiating factor (I do think other factors may of been involved too but were less obvious. I had several Hep B vaccinations that year etc so who knows what that role that played mixed with stress. Stress triggering off ME/CFS and a crash was the obvious trigger thou, it only would take me a few days of hard study to get sick).

I do think its important due to this that doctors seeing ME/CFS patients warn to try to keep the stress levels down. It should be recognised that we need to take things easy.

 

[taniaaust1]

Perhaps I should have highlighted very flexible as well!

Seriously though, when it comes to activity/energy management, one place where we could start is by looking at what strategies people have used (successfully and not successfully) in the very early stages of ME/CFS - i.e. in the days, weeks, months following the onset of their ME/CFS

Most of my medical colleagues don't have a clue when it comes to advising people on activity/energy management when an infective episode has triggered some form of persisting post infectious fatigue, or the possibility that they may have developed ME/CFS

1/ early activity or exercise advice, thou I'd assume would be based on how ill the infective episode has left the person (though since when do ill people get told to exercise? maybe that suggestion is wrong in itself early illness)

2/ unfortunately much of the time judging how sick another is, can be extremely hard and how do you really teach that? and without knowing this, how would a dr know how much activity is advisable? (wouldnt the sick person themselves be the best judge of this? after all we all experience every day people thinking we can safely do more then we can even at times from ME/CFS specialists!).

I think studying that in the hopes that drs can be taught how to advise activity levels to those with ME/CFS is barking up the wrong tree as too much of it when other is trying to work out how sick a ME/CFS person is i subjective (unless they have something objective to use to test us).

I think they'd be better off studying the "whys" of why so many of us get worst with exercise, so they can put sensitive plans in place to prevent this rather then trying judge how much exercise or activity each of us should do.

Yes ME/CFS management study may be good for early illness but I dont think it should be focused on activity/exercise.

 

[taniaaust1]

I've posted about my 4 data points on this before.

• I had ME/CFS when young. I mostly rested and I recovered in a year.
• I was well until my late 40's when I became ill again. I mostly stayed active and, although I'm better than I was, I am still quite affected.

So far the data points support the 'rest is best' camp. BUT

• My son got ME/CFS at the same time as my second bout. He mostly rested as his joint pain was quite severe. He is still sick.
• My daughter got ME/CFS at the same time too. She mostly kept active. She recovered to nearly 100% in two years.

So, even with similar genetics and the same illness, there is no recovery pattern related to whether we rested or remained active.

If you combine that sort of variability with a study population that may well include different diseases and certainly different subsets and throw in a researcher or two who has a preconceived idea of what the outcome should be; I think you have a recipe for unhelpful research.

nods, I too think there may not be one easy answer esp when they are refering to early CFS or at a time before a ME/CFS diagnoses is there. Its probably just a waste of research money that area when there is so much more which could be focused on. All I can be sure on early illness is that its probably very bad for someone to actually be pushing themselves to exercise while ill (if the person is comfortable still to exercise while ill and is without further problems, I dont see why a dr or anyone else should tell someone to stop).