Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Ninan]

Thanks so much @Jonathan Edwards for being here and answering questions. It really means a lot.

I am trying Methorexate, beginning next week, for ME/CFS. I’m a pretty severe case, bedbound most of the time with extreme sensitivity to noise and light (I’m on a kind of weird combo of drugs right now and that’s why I can use my computer, but it only lasts for a couple of months at a time). I also have a mild case of psoriasis, I’ve had double sided joint inflammation (when exercising, so I obviously don't have them anymore) since I was ten and lots of autoimmunity in my family (RA, AS, MS etc). I know there are lots of different opinions on whether trying a drug like this is a smart move or not but I haven’t had a cold or a flu for seven years (I felt much better when I did) and I haven't found anyone with ME/CFS who got worse from methotrexate. Not expecting much more than nausea though. (I have a wonderful doctor who’ll be keeping an eye on my blood works etc.)

My question which I’m sure you’ve heard before is about what medicines out there could be worth studying. We’re all pretty anxious about getting on with our lives and if there are any relatively cheap, easy administered immunomodulators or -suppressants maybe we could have some more trials like the Dutch one with Anakinra.

Methotrexate is one. We know it helped one of the patients who responded to rituximab in the first Norwegian trial (not sure what dose they got, though) and there are stories of people recovering completely even though most ME/CFS-patients who receive it for psoriasis etc don’t seem to have much of an effect. Another one that I’ve found while following the MS field is Tecfidera (dimethyl fumarate). It’s a drug that’s been used to treat psoriasis and is now approved for relapsing forms of MS.

Do you think Tecfidera could be a candidate for ME/CFS-treatment? And are there any other drugs out there that fit the description? I understand completely that you cannot recommend anyone to try drugs when there is no research (some say we have nothing to lose, but I'm bed bound and still have a lot) but it would be interesting to hear if there are more like these out there and if you have any idea whatsoever about which ones would be worth a study. Thanks!

 

[Kati]

Good luck with methotrexate, @Ninan, let us know how it goes.

Do you know if you will be on a dosage similar to RA?

 

[NK17]

Cross my fingers for you @Ninan and wish you a long stretch remission with the methotrexate treatment.

Please report on PR whenever you can.

 

[Ninan]

@Kati Yes, I'll take the standard RA dose, starting low.

@NK17 Thanks. I'll keep you posted.

 

[catly]

@Ninan Good luck and please keep us posted.

I've had 2 rheumatologists suggest that I start placquenil or possibly methotrexate treatment because of my +ANA, high TPO (hashimotos thyroiditis), low+ CCP (antibodies for RA) and sicca syndrome. All this coincided with onset of ME.

I never started the treatment because I started on the path of antivirals and LDN as recommended by my ME/CFS specialist.

I would do it in a heartbeat if I thought it might help.

 

[Ninan]

This post is kind of interesting. A woman who suffered from CFS was helped by the following regime:

Methotrexate 10mg once a week
Leflunomide 10mg daily
Prednisone 5mg daily
Folic Acid 5mg six days (miss on the Methotrexate day)
Blackmores Sustained Release MultiVitamin 1 a day

http://www.healthboards.com/boards/chronic-fatigue/858866-help-last-cfs-sufferers.html

 

[Jonathan Edwards]

Dear Ninan,
I do not know of tecfidera I am afraid. It is hard to say what other drugs to recommend even if one guesses thatthere may be an autoimmune basis. Methotrexate works in RA at a dose that is too low really to be very immunosuppressive - nobody knows how it works I think. Azathioprine has often been used in the past for immune disorders but I gave up using it because of worries about skin cancers. The reason why, like Drs Fluge and Mella, I am interested in rituximab is that we know exactly what it does and so if it works it will tell us where else to look. There are other anti-B cell agents like belimumab, but quite when they would be helpful is still uncertain.

So I am not sure I am much help on this one. At least methotrexate seems worth a try since Dr Fluge noted an improvement in one of his cases.

 

[Kate_UK]

Fundraising for the UK trial is now at £347,046 of £350,000. Less than £3000 until target.

 

[Min]

Fundraising for the UK trial is now at £347,046 of £350,000. Less than £3000 until target.

Yabadabadoo!

 

[Ninan]

Dear Ninan,
I do not know of tecfidera I am afraid. It is hard to say what other drugs to recommend even if one guesses thatthere may be an autoimmune basis. Methotrexate works in RA at a dose that is too low really to be very immunosuppressive - nobody knows how it works I think. Azathioprine has often been used in the past for immune disorders but I gave up using it because of worries about skin cancers. The reason why, like Drs Fluge and Mella, I am interested in rituximab is that we know exactly what it does and so if it works it will tell us where else to look. There are other anti-B cell agents like belimumab, but quite when they would be helpful is still uncertain.

So I am not sure I am much help on this one. At least methotrexate seems worth a try since Dr Fluge noted an improvement in one of his cases.

I wonder if the RA dose for MTX isn't too small. I've found four or five cases of PWME:s getting better from it and all but one or two of them received higher doses, while treating lymphoma or for other reasons. Olof Zachrisson at the Gottfries clinic says he has had many patients on MTX for psoriasis and RA and he has never heard of any of them having any effect on their ME symptoms. If it was common I think we'd know about it. It's not a rare medication.

Does anyone know how sure the researchers are that it’s B-cell depleting effect from rituximab that is causing the effect? Could it be something else? (I know there’s the EBV theory but in that case the effect would also come from depleting B-cells.) It seems all medications aimed directly at depleting B-cells are very expensive and complicated to administer.

Azathioprine seems pretty nasty but interesting, @Jonathan Edwards. Maybe if it was used for ME one wouldn’t have to give it during such a long time?

A friend of mine who’s a neurologist mentioned Purinethol. From what I understand they both lower the number of B-cells and are given to patients who’s had a transplantation and to patients with autoimmune disorder under the course of many years, hence causing severe side effects. (I read somewhere that about 50-95 percent of transplantation patients had developed cancer 20 years after the transplantation and that there was a strong suspicion that this was because of the immunosuppressive medications. That’s a huge number.)

But if one would try to use Azathioprine for ME, maybe the course of treatment could be shorter? Instead of giving it as a long-term maintenance therapy you could try to imitate the rituximab-therapy given at Haukeland. Start depleting B-cells and when they’re down to a certain number simply stop the treatment and see if there is an effect after 2-8 months. If these medications do about the same thing as rituximab (though I guess they do other things too) and if B-cell depletion is the reason rituximab is working, then maybe you could expect about the same result. The course would have to be repeated if the patient got worse again but the risk of getting serious side effects like cancer would probably be much smaller if the treatment wasn’t long term, right? (From what I've read the risk of getting skin cancer is so much bigger because patients get extremely sensitive to UV light while on the medication, not because of some long lasting effects. But they don't seem to be a 100 per cent sure.)

I guess rituximab is the better alternative since you know exactly what it does. But when given in shorter courses maybe the risks with these other medicines would be about the same as with rituximab? And the costs very much smaller, which is important to us since doctors are much more willing to use a medication off label if it doesn’t cost a fortune. Even if it’s not as effective and has more potential side effects than the expensive one.

 

[Jonathan Edwards]

Rituximab definitely works by depleting B cells. It has no consistent effect on anything else as far as we know and one would not expect it to, which makes it so useful as a help to understanding mechanism. Azathioprine does not work by depleting B cells, which change rather little on azathioprine, so I do not see any prospect of it being useful in short bursts. It also makes quite a lot of people nauseous.

 

[Ninan]

Bummer. Thought I had solved it. I guess if there was a cheap alternative doing about the same thing, rituximab wouldn't exist.

Anyway I'm starting MTX on Monday, 2,5 mg and raising 2,5 every week if I tolerate it ok. I think my doctor wants to go as high as 7,5 mg/week. The woman in the Fluge/Mella study had an effect from 10 mg, but she started it while having effect from rituximab so I guess our starting points are quite different. For her it lasted for 25 weeks. I'm hoping for a miracle but expecting nausea. If anyone is interested I’ll be updating here.

 

[NK17]

Bummer. Thought I had solved it. I guess if there was a cheap alternative doing about the same thing, rituximab wouldn't exist.

Anyway I'm starting MTX on Monday, 2,5 mg and raising 2,5 every week if I tolerate it ok. I think my doctor wants to go as high as 7,5 mg/week. The woman in the Fluge/Mella study had an effect from 10 mg, but she started it while having effect from rituximab so I guess our starting points are quite different. For her it lasted for 25 weeks. I'm hoping for a miracle but expecting nausea. If anyone is interested I’ll be updating here.

Good luck @Ninan. I'll follow your treatment's report .

 

[MeSci]

Bummer. Thought I had solved it. I guess if there was a cheap alternative doing about the same thing, rituximab wouldn't exist.

Don't give up trying - you never know!

 

[aimossy]

@Jonathan Edwards I'm wondering what you think of this. Its from the latest article on here about the invest in ME conference.

Finally, Hornig offered an update on the very latest state of play with their ME/CFS research work. They were just about to start a pilot study through the Chronic Fatigue Initiative (so this should be well under way by the time of writing), searching in white blood cells, and ‘hot off the press’ their study of 180 metabolites has found that short duration ME/CFS patients (those in the first few years of illness) are showing significantly reduced levels of ADMA (asymmetric dimethylarginine). This could be quite significant, because this would cause oxidative stress – and as she noted earlier, that could be a key factor in promoting autoimmunity.

I was wondering about this ADMA, I remembered some of the discussions about the theory of NO and endothethial function, but to be honest my brain looses information. I googled this ADMA and of course one thing does not necessarily relate to another. I'm really just wondering what you make of it, I know its all theoretical but I found this interesting.

 

[Snow Leopard]

The above statement is from Mark Berry's article, rather than the IIME website. The finding is interesting, but still unknown what it really means. My question would be, did they control for B vitamin supplementation as that could be a mediator of those findings.

There was however a study that found elevated levels of asymmetric dimethylarginine levels in Fibromyaligia, which was also correlated with TNF-α levels.

http://www.sciencedirect.com/science/article/pii/S0009912011000397

That article came up in Google scholar since I was searching for asymmetric dimethylarginine and fatigue.

Edit additionally: Increased asymmetric dimethylarginine levels have also been found in depression (and decreased Nitric Oxide too).

Oh and I am very glad to hear the Rituximab study is more or less completely funded now!

 

[Jonathan Edwards]

@Jonathan Edwards I'm wondering what you think of this. Its from the latest article on here about the invest in ME conference.

I was wondering about this ADMA, I remembered some of the discussions about the theory of NO and endothethial function, but to be honest my brain looses information. I googled this ADMA and of course one thing does not necessarily relate to another. I'm really just wondering what you make of it, I know its all theoretical but I found this interesting.

Mady Hornig is doing some very interesting work at present. I have to say I did not pick up on this molecule, which Mark noted her report on. It is not something I know enough about to comment on really.

 

[Mark]

Mady Hornig is doing some very interesting work at present. I have to say I did not pick up on this molecule, which Mark noted her report on. It is not something I know enough about to comment on really.

I hope I got it right. As I remember it, this was the only thing in her talk that sounded like new info, so I took special pains to take accurate notes, and I'm pretty sure the words "hot off the press" were Mady's own words. I haven't even looked up what ADMA is, but if there's an endothelial connection then that sounds potentially exciting to me.

 

[aimossy]

Thanks @Jonathan Edwards ,
When I read about it in Mark's article (thanks Mark ) I googled ADMA and wondered if this could have some affect on NO and endothelial function. I thought 'far out', has Mady Hornig possibly found something that could support the theory that Fluge or Mella have. ( I'm sorry I couldn't remember which doctor of the two had the theory).
It's pretty neat when you see something that might translate across peoples research or theories. I know its theoretical, but still - I thought it was a very neat idea and was very excited for a whole day! I am just hoping to hear more about it.

 

[Marco]

Re ADMA (which I'd never heard of previously) elevated ADMA appears to be associated with various pathologies and the only example I could find where AMDA is low is in premature infants with necrotizing enterocolitis :

Low plasma concentrations of arginine and asymmetric dimethylarginine in
premature infants with necrotizing enterocolitis

Necrotizing enterocolitis (NEC), is the most common gastrointestinal
emergency in the premature infant (Neu, 1996).
Although NEC is a multifactorial disease, prematurity is a
main risk factor. Mucosal injury resulting from ischemia, bacterial
colonization and early enteral feeding are also recognized
as potentially important contributors to the pathogenesis of
NEC (Kliegman et al. 1993; Neu, 2005).

Reduced arginine (not reported by Hornig?) and ADMA may be a risk factor or result from gastrointestinal infection or impaired gut microcirculation :

These animal studies indicate that a low
plasma concentration of arginine, and inhibition of the arginine–
NO pathway, could contribute to decreased synthesis of
NO, thereby resulting in decreased gastrointestinal blood flow
and impairment of the intestinal mucosal barrier.

Interestingly, in contrast to our hypothesis, a significantly
lower ADMA concentration was found in premature infants
with NEC. Because ADMA is an endogenous inhibitor of all
isoforms of NOS, a decrease of ADMA in premature infants
with NEC could be associated with attempted regulatory
changes aimed at a preservation of NO production in the presence
of low arginine concentrations.

Although we cannot designate a single mediator for the
observed effect, theoretically an increased metabolic turnover
of ADMA may be responsible for the lower levels in NEC
patients. ADMA is eliminated from the body by renal
excretion as well as being metabolized by the enzyme
dimethylarginine dimethylaminohydrolase (DDAH) which is
widely distributed, in particular in the pancreas, liver and
kidney (Kimoto et al. 1993; Kimoto et al. 1995).

Induction of this enzyme or an increased renal excretion in NEC patients
could be responsible for the decreased ADMA concentration
(Yudkoff et al. 1984; Kimoto et al. 1995). Nijveldt and coworkers
(Nijveldt et al. 2003b; Nijveldt et al. 2004) showed
a reduced systemic ADMA concentration in rats during endotoxemia,
indicating increased DDAH activity. Also, acute
Escherichia coli endotoxaemia in human subjects decreased
the plasma arginine:ADMA ratio (Mittermayer et al. 2004).

http://www.ncbi.nlm.nih.gov/pubmed/17381965

I wonder if the ADMA finding partly explains Hornig and Lipkin's interest in the gut microbiome?