Re: RESEARCH - The melatonin-cytokine connection in RA

[Guest guest]

Melatonin Serum Levels in Rheumatoid Arthritis

aLaboratory and Division of Rheumatology, Department of Internal

Medicine and Medical Specialities, University of Genova, Genova, Italy

bIstituto Cantonale di Patologia, Center for Experimental Pathology,

Locarno, Switzerland

Abstract:

The pineal hormone melatonin (MLT) exerts a variety of effects on the

immune system. MLT activates immune cells and enhances inflammatory

cytokine and nitric oxide production. Cytokines are strongly involved

in the synovial immune and inflammatory response in rheumatoid

arthritis (RA) and reach the peak of concentration in the early

morning, when MLT serum level is higher. Nocturnal MLT serum levels

were evaluated in 10 RA patients and in 6 healthy controls. Blood

samples were obtained at 8 and 12 p.m., as well as at 2, 4, 6, and 8

a.m. MLT serum levels at 8 p.m. and 8 a.m. were found to be higher in

RA patients than in controls (p < 0.05). In both RA patients and

healthy subjects, MLT progressively increased from 8 p.m. to the first

hours of the morning, when the peak level was reached (p < 0.02).

However, MLT serum level reached the peak at least two hours before in

RA patients than in controls (p < 0.05). Subsequently, in RA patients,

MLT concentration showed a plateau level lasting two to three hours, an

effect not observed in healthy controls. After 2 a.m., MLT levels

decreased similarly in both RA patients and healthy subjects. Several

clinical symptoms of RA, such as morning gelling, stiffness, and

swelling, which are more evident in the early morning, might be related

to the neuroimmunomodulatory effects exerted by MLT on synovitis and

might be explained by the imbalance between cortisol serum levels

(lower in RA patients) and MLT serum levels (higher in RA patients).

[Guest guest]

Ok, I'm confused.

At one point this article is saying that " Melatonin regulates

cytokine production and immune function " and " MLT possesses important

immunoenhancing properties " which sounds like Melatonin could be a

positive factor in RA (an auto-immune disorder).

BUT, at the end of the article, it talks about " ...the ability of MLT

to enhance production of inflammatory cytokines... " and THAT is the

part that concerns and confuses me. Especially if someone were to be

taking Melatonin supplements as a sleep aid.

Wikipedia says " Overstimulation of cytokines can trigger a dangerous

syndrome known as a cytokine storm... " which " ...can occur in a

number of diseases... " including " ...systemic inflammatory response

syndrome (SIRS)... " " ...an inflammatory state of the whole body

(the " system " ) without a proven source of infection. "

My concern here is that while this article may show that

Melatonin " naturally " produced by the body can have positive effects

on RA, it MAY BE giving the impression that supplementing the body

with Melatonin COULD HAVE the opposite (and negative) effects

by " Overstimulation of cytokines " .

Is there a doctor in the house that could shed some light on this

article in " layman " terms? I would be interested to know if the

Melatonin supplements that I take as a sleep aid (15mg/day) could be

causing increased inflammation in my body and therefore MIGHT explain

why my RA is not controlled.

Thanks........Doreen

NOT a Medical Professional

[Guest guest]

Mimi,

I posted this article because Sue wondered what effects melatonin

might have on RA.

The take-home message was the heading: " Melatonin up regulates

cytokine production and immune function " - two things you probably

don't want to do if you have RA.

You dont' necessarily want to " rev up " an immune system that is attacking you.

Two of the cytokines linked with RA with which you are probably most

familiar are tumor necrosis factor (TNF) and interleukin (IL).

I believe it would be highly unlikely to induce a cytokine storm with

a melatonin supplement taken as directed. I think there is evidence

though that it might not be helpful for RA patients and even

counterproductive.

Your rheumatologist should be aware that you are taking it. Do discuss

it with him/her.

Not an MD

On Fri, May 30, 2008 at 6:27 AM, Mimi <mimi212@...> wrote:

> Ok, I'm confused.

>

> At one point this article is saying that " Melatonin regulates

> cytokine production and immune function " and " MLT possesses important

> immunoenhancing properties " which sounds like Melatonin could be a

> positive factor in RA (an auto-immune disorder).

>

> BUT, at the end of the article, it talks about " ...the ability of MLT

> to enhance production of inflammatory cytokines... " and THAT is the

> part that concerns and confuses me. Especially if someone were to be

> taking Melatonin supplements as a sleep aid.

>

> Wikipedia says " Overstimulation of cytokines can trigger a dangerous

> syndrome known as a cytokine storm... " which " ...can occur in a

> number of diseases... " including " ...systemic inflammatory response

> syndrome (SIRS)... " " ...an inflammatory state of the whole body

> (the " system " ) without a proven source of infection. "

>

> My concern here is that while this article may show that

> Melatonin " naturally " produced by the body can have positive effects

> on RA, it MAY BE giving the impression that supplementing the body

> with Melatonin COULD HAVE the opposite (and negative) effects

> by " Overstimulation of cytokines " .

>

> Is there a doctor in the house that could shed some light on this

> article in " layman " terms? I would be interested to know if the

> Melatonin supplements that I take as a sleep aid (15mg/day) could be

> causing increased inflammation in my body and therefore MIGHT explain

> why my RA is not controlled.

>

> Thanks........Doreen

> NOT a Medical Professional

>

>

>

>

>

>

>

>

>

> ------------------------------------

>

>

[Guest guest]

Thanks, . I hope I didn't offend you with my reply. I

appreciate you clarifying the melatonin/RA combo with me. After

reading the article that you posted, I decided to stop taking the

Melatonin and see how long it would take me to feel a difference.

Well, this morning was the first wake up after no Melatonin and while

I was still hurting as usual, the pain was different. So, I think I

may have been shooting myself in the foot by taking it. Time will

tell as I am sure that its going to take more than one wake up to

know if stopping it will do any good. But, if I am not needing it to

go to sleep, then there is not sense in taking it anyway and if I

find I am having difficulties again, I'll call my doctor. (Sorry,

talking out loud here)

I'm not happy with the Rheumatologist that I have been seeing for

over a year now, but unfortunately he is the only one around this

area without having to drive 30-45 minutes to find another one. I

have brought in my meds sheet with every visit, but his office

personnel seem to overlook the OTC stuff. I will definitely bring

this to his attention next visit.

Thanks again,

Doreen

[Guest guest]

Hi, Doreen.

No, I wasn't at all offended. Sorry if you thought I might have been. It's

so hard to convey tone in these darn E-mails.

Sorry you aren't satisfied with your current rheumatologist. I'm glad you'll

talk to him about the melatonin. Please let us know what he thinks.

Not an MD

> [ ] Re: RESEARCH - The melatonin-cytokine connection in

RA

>

> Thanks, . I hope I didn't offend you with my reply. I

> appreciate you clarifying the melatonin/RA combo with me. After

> reading the article that you posted, I decided to stop taking the

> Melatonin and see how long it would take me to feel a difference.

> Well, this morning was the first wake up after no Melatonin and while

> I was still hurting as usual, the pain was different. So, I think I

> may have been shooting myself in the foot by taking it. Time will

> tell as I am sure that its going to take more than one wake up to

> know if stopping it will do any good. But, if I am not needing it to

> go to sleep, then there is not sense in taking it anyway and if I

> find I am having difficulties again, I'll call my doctor. (Sorry,

> talking out loud here)

>

> I'm not happy with the Rheumatologist that I have been seeing for

> over a year now, but unfortunately he is the only one around this

> area without having to drive 30-45 minutes to find another one. I

> have brought in my meds sheet with every visit, but his office

> personnel seem to overlook the OTC stuff. I will definitely bring

> this to his attention next visit.

>

> Thanks again,

> Doreen

[Guest guest]

Inflammatory status and kynurenine metabolism in rheumatoid arthritis

treated with melatonin

Authors: Forrest, Caroline M.; Mackay, Gillian M.; Stoy, 1;

Stone, Trevor W.; Darlington, L. Gail1

Source: British Journal of Clinical Pharmacology, Volume 64, Number 4,

October 2007 , pp. 517-526(10)

Publisher: Blackwell Publishing

Abstract:

What is already known about this subject

• There is good evidence that oxidative stress, associated with the

generation of free radicals, is a major contributor to joint damage in

rheumatoid arthritis.

• It is also well established that melatonin is one of the most

powerful, endogenous free radical scavengers, and it is very safe for

human use.

• We have therefore examined whether melatonin might be a useful

adjunctive compound with which to treat arthritis.

What this study adds

• Once-nightly administration of melatonin increases concentrations of

some inflammatory markers, but patients experience no significant

improvement in symptoms and no changes of proinflammatory cytokine

concentrations.

• Melatonin is an effective antioxidant, but because it is either not

sufficiently effective, or it has some proinflammatory activity, it is

not likely to prove beneficial in patients. Aim

Since melatonin is antioxidant and has some anti-inflammatory actions,

we have tested it as adjunctive treatment in patients with rheumatoid

arthritis, to determine whether it can improve patients' symptoms.

Methods

A total of 75 patients were allocated randomly to receive melatonin

10 mg at night in addition to ongoing medication, or a placebo of

identical appearance. Monthly blood samples were taken and disease

severity assessed over 6 months, plasma being analysed for inflammatory

indicators [C-reactive protein, erythrocyte sedimentation rate (ESR),

neopterin], proinflammatory cytokines [interleukin (IL)-1β, IL-6,

tumour necrosis factor (TNF)-α], lipid peroxidation products and the

kynurenine pathway metabolites of tryptophan. Results

An increase of ESR (two-wayanovaF(1,127) = 5.24, P = 0.024) and

neopterin concentrations (F(1,136) = 4.64, P = 0.033) was observed in

treated patients compared with controls, reflected also in a

significant trend for both to decline in placebo-treated patients

(P = 0.022), but not the melatonin-treated group. Peroxidation products

showed a significant trend to decrease in placebo- but not

melatonin-treated patients. These results suggest a proinflammatory

action, but there were no significant effects of melatonin treatment on

clinical assessments of patient symptoms or the concentrations of three

proinflammatory cytokines, IL-1β, IL-6 and TNF-α. Melatonin

significantly increased plasma kynurenine concentrations

(F(1,124) = 4.24, P = 0.041), again suggesting proinflammatory

activity. Conclusion

A daily dose of 10 mg melatonin shows a slowly developing antioxidant

profile in patients with arthritis and increases the concentrations of

some inflammatory indicators, but these effects are not associated with

any change of proinflammatory cytokine concentrations or clinical

symptoms.

[Guest guest]

And I posted some more articles because I was still trying to

understand. They seemed to be saying that people with RA have too much

melatonin already. Is that why I seem to need so much sleep?

Then I found another article that said we don't have enough melatonin:

" Melatonin levels are lower in patients with rheumatoid arthritis than

in healthy individuals without arthritis. However, when arthritis

patients were treated with the anti-inflammatory medication

indomethacin, melatonin levels returned to normal. The chemical

structure of melatonin resembles indomethacin, so researchers suspect

that melatonin supplements may work similarly to this medication for

people with rheumatoid arthritis. However, this theory has not been

tested. "

I'll post one other article that I found in another post.

Sue

On Saturday, May 31, 2008, at 09:18 AM, wrote:

> Mimi,

>

> I posted this article because Sue wondered what effects melatonin

> might have on RA.

>

> The take-home message was the heading: " Melatonin up regulates

> cytokine production and immune function " - two things you probably

> don't want to do if you have RA.

>

> You dont' necessarily want to " rev up " an immune system that is

> attacking you.

>

[Guest guest]

Hi, ! the reasons you give here are exactly why I will NOT take

echineah tablets for a head cold...don't need to rev up the immune

system, for sure! Marcia, in New York State

--- <Rheumatoid.Arthritis.Support@...> wrote:

> Mimi,

>

> I posted this article because Sue wondered what effects melatonin

> might have on RA.

>

> The take-home message was the heading: " Melatonin up regulates

> cytokine production and immune function " - two things you probably

> don't want to do if you have RA.

>

> You dont' necessarily want to " rev up " an immune system that is

> attacking you.

>

> Two of the cytokines linked with RA with which you are probably most

> familiar are tumor necrosis factor (TNF) and interleukin (IL).

>

> I believe it would be highly unlikely to induce a cytokine storm with

> a melatonin supplement taken as directed. I think there is evidence

> though that it might not be helpful for RA patients and even

> counterproductive.

>

> Your rheumatologist should be aware that you are taking it. Do

> discuss

> it with him/her.

>

>

>

> Not an MD

>

>

>

> On Fri, May 30, 2008 at 6:27 AM, Mimi <mimi212@...> wrote:

> > Ok, I'm confused.

> >

> > At one point this article is saying that " Melatonin regulates

> > cytokine production and immune function " and " MLT possesses

> important

> > immunoenhancing properties " which sounds like Melatonin could be a

> > positive factor in RA (an auto-immune disorder).

> >

> > BUT, at the end of the article, it talks about " ...the ability of

> MLT

> > to enhance production of inflammatory cytokines... " and THAT is the

> > part that concerns and confuses me. Especially if someone were to

> be

> > taking Melatonin supplements as a sleep aid.

> >

> > Wikipedia says " Overstimulation of cytokines can trigger a

> dangerous

> > syndrome known as a cytokine storm... " which " ...can occur in a

> > number of diseases... " including " ...systemic inflammatory response

> > syndrome (SIRS)... " " ...an inflammatory state of the whole body

> > (the " system " ) without a proven source of infection. "

> >

> > My concern here is that while this article may show that

> > Melatonin " naturally " produced by the body can have positive

> effects

> > on RA, it MAY BE giving the impression that supplementing the body

> > with Melatonin COULD HAVE the opposite (and negative) effects

> > by " Overstimulation of cytokines " .

> >

> > Is there a doctor in the house that could shed some light on this

> > article in " layman " terms? I would be interested to know if the

> > Melatonin supplements that I take as a sleep aid (15mg/day) could

> be

> > causing increased inflammation in my body and therefore MIGHT

> explain

> > why my RA is not controlled.

> >

> > Thanks........Doreen

> > NOT a Medical Professional

> >

> >

> >

> >

> >

> >

> >

> >

> >

> > ------------------------------------

> >

> >

[Guest guest]

Thanks, ladies for all of this good information. I have now been two

nights without my melatonin supplements (15mg) and I can honestly say I

feel the difference - my morning stiffness and pain isn't as severe. I

think (for me) this confirms the conclusion of this study Sue

posted. Thank you and please forgive me for getting up in the middle

of this......Doreen

" A daily dose of 10mg melatonin shows a slowly developing antioxidant

profile in patients with arthritis and increases the concentrations of

some inflammatory indicators, but these effects are not associated with

any change of proinflammatory cytokine concentrations or clinical

symptoms "