Immunosuppresant vs. Immunomodulator

[Special Kay]

I hope the biochemists out there (amateur or professional) can clear something up for me.

One of the risk criteria for Tysabri is "prior use of immunosuppressant medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil)."

What is the distinction between an immunomodulator and an immunosuppressant? It seems to me that "immunosuppressant" should be a subcategory of "immunomodulator."

What I'm trying to clarify is whether prior interferon (immunomodulator) use fulfills the Tysabri risk criteria, even though it's not one of the examples given.

[22cyclist]

I hope the biochemists out there (amateur or professional) can clear something up for me.

One of the risk criteria for Tysabri is "prior use of immunosuppressant medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil)."

What is the distinction between an immunomodulator and an immunosuppressant? It seems to me that "immunosuppressant" should be a subcategory of "immunomodulator."

What I'm trying to clarify is whether prior interferon (immunomodulator) use fulfills the Tysabri risk criteria, even though it's not one of the examples given.

I am definitely not a biochemist, but I am an RN, so I will take a stab: Prior interferon use does not fulfill the risk criteria unless you have bone marrow failure, for which you will be checked. If any of your counts are low, you will be given time to recover. I am going to give a list of common meds used in MS and what they do. Hopefully not TMI. I left out some of the newer pills on purpose.

Immunomodulators for the purpose of MS:

1. Interferon beta 1-a (Rebif; Avonex): Works by modifying the immune system. The exact mechanism is unknown. Beta 1-a inhibits the expression of proinflammatory cytokines like interferon gamma which is believed to be a major trigger in the immune response leading to MS.

2. Interferon beta 1-b (Betaseron; Extavia): Again works by modifying the immune system. Exact mechanism is unknown. Beta 1-b is thought to inhibit proinflammatory cytokines including: interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha and TNF-beta, interferon gamma (IFN-γ), and IL-6. IFN-γ is believed to be a major factor responsible for triggering the autoimmune reaction leading to MS.

3. Glatiramer (Copaxone): Synthetic amino acid copolymer; precise mechanism unknown but possibly through immune modulation; may interfere with antigen presenting function of some immune cells opposing pathogenic T-cell function; may also activate T-lymphocyte suppressor cells specific for myelin antigen.

4. Fingolimod (Gilenya): Sphingosine 1-phosphate receptor modulator; metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate.

Binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5; blocks lymphocyte capacity to egress from lymph nodes, and thereby reduces the lymphocyte count in peripheral blood

The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system

5. BG-12: The exact mechanism of action is not yet completely understood but is thought to occur the following way:

BG-12 has been found able to switch the T-helper response from Th1 to Th2 phenotype, both increasing the Th2 driving molecules, such as IL-4, IL-10, and IL-5, and reducing the Th1 driving molecules, IL-6, IL-1β and tumor necrosis factor (TNF) alpha. The second pathway involves the activation of the nuclear factor E2-related factor 2 (Nrf2) transcriptional pathway, which acts on one side as an oxidative stress modulator by the induction of phase II detoxification genes.

Treatment of cultured astroglia and microglia with fumaric acid esters enhances the activity of phase II detoxification enzyme NAD(P)H:quinone oxidoreductase-1 (NQO-1) mRNA, and increases the cellular glutathione content of activated mixed glial cells. On the other side the Nrf2 has neuroprotective capabilities such as inhibition of excitotoxic and oxidative neuronal damage. Blood brain barier protection and regulation of myelin maintenance. through the third pathway, DMF almost completely inhibits the TNF-induced CD62E, responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. These data suggest that BG-12 could have dual neuroprotective and anti-inflammatory effects.

IMMUNOSUPPRESSANTS: For the purpose of MS, or otherwise for that matter, work to suppress the white blood cell count, not modify it as an immune modifier does.

1. Natalizumab (Tysabri): Is a monoclonal antibody to the α4 subunit of α4β1 integrin (VLA-4), a protein found on the surface of lymphocytes. α4β1 integrins interact with the vascular-cell adhesion molecule 1 enabling adhesion of lymphocytes to the vascular endothelium. Its main mode of action is to prevent the transmigration of inflammatory lymphocytes across the blood brain barrier into the CNS.

Higher level immunosuppressants are sometimes used in secondary progressive MS:

1. Azathioprine (Azasan, Imuran): Azathioprine is generally used in the treatment of transplant rejection or severe, active, erosive rheumatoid arthritis, but it has been used off-label for MS. It can severely weaken the immune system to the point of bone marrow failure.

2. Methotrexate (Rheumatrex): Methotrexate interferes with DNA synthesis, repair, and cellular replication. It inhibits dihydrofolic acid reductase, which participates in the synthesis of thymidylate and purine nucleotides. Methotrexate has been used off-label for MS.

CHEMOTHERAPUTIC AGENTS: These are immunosuppressants by nature in most cases but are in a class by themselves as they are more potent than the ones above.

1. Mitoxantrone (Novantrone): Mitoxantrone is an immunosuppressive agent approved for the treatment of secondary progressive or aggressive relapsing-remitting MS. It is used for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (long-term) progressive, progressive relapsing, or worsening relapsing-remitting MS (ie, patients whose neurologic status is significantly abnormal between relapses). Mitoxantrone is not indicated in the treatment of patients with primary progressive MS.

Mitoxantrone therapy can increase the risk of developing secondary acute myeloid leukemia (AML) in MS patients and in patients with cancer.

2. Cyclophosphamide: Cyclophosphamide has been used for the treatment of progressive MS. Evidence of benefit is mixed. This agent has not been approved for MS but has been used off-label in MS patients. Cyclophosphamide is associated with leukemia, lymphoma, infection, and hemorrhagic cystitis.

As a side note: I have a friend with PPMS that takes this drug and has had good results. There were no other options for him.

After all of this fluff, the thing is, immunomodulators generally augment the immune system, not suppress it.
So if a person has a low white count for instance, in immune modulator might help their count normalize if it is not too low; likewise, a person whose count is too high may benefit as it might lower their count. A person with a normal count will likely have no effect.

If you give a normal person an immunosuppressant, it will suppress the immune system. It will not augment the cells in any way to help boost the white count as the purpose is to keep try to lower it and keep it in check.

For the purpose of Tysabri, the main concern with prior use of immunosuppressants is the risk of PML. Immunodmodulator use has not shown this risk so it is not a factor unless your bone marrow is suppressed in which case you will not be placed on the medication until it recovers.

My sources are:
http://emedicine.medscape.com/articl...9-medication#6
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100222/

[Redwings]

Hi Special Kay:

It sounds like you have a basic idea of the definitions. An immunomodulator makes adjustments to some aspect of the immune system. The adjustment can be an increase or decrease in a chemical or cell, or an alteration of the way a chemical or cell behaves. For example, Copaxone is believed to modulate the immune system by essentially acting as a decoy that draws T cells (a type of white blood cell) away from myelin. That action doesn’t strengthen or weaken the T cells, it just lures them away.

You’re right in that immunosuppressants are a subcategory of immunomodulators. They suppress the production of T and B blood cells by interfering with their multiplication. This action is very specific, so the custom is to refer to immunosuppressants and immunomodulators separately to distinguish the immunosuppressant category.

The interferons used for MS don’t suppress white blood cell production and aren’t included in the immunosuppressant category. (The interferons can have some other blood cell effects, but that’s outside the scope of your question.) That’s why they’re not contraindications for Tysabri treatment.

Actually, right up until recently, when the risk factors for PML became more clearly defined, it was strongly recommended that Tysabri not be used unless and until the CRAB drugs (3 of the 4 which are interferons) were tried first. That’s the opposite of a contraindication. So obviously the interferons are not included among the immunosuppressants as a known risk factor.

When Tysabri was first in clinical trials, Biogen was testing it in concurrent use with its other MS drug Avonex. When PML began showing up in Tysabri users, it wasn’t clear whether the cause was Tysabri or the combination. As the Tysabri-PML connection became better understood, the increased risk was attributed to immunosuppressants and not the immunomodulatory CRAB drugs.

When Tysabri was returned to the marketplace, it was deemed appropriate only as a monotherapy – no other immunomodulatory drugs to be used with it. But, again, the CRAB drugs were not only allowed (because they didn’t appear to be a risk factor for PML) but encouraged to be used before Tysabri.

In a nutshell, use of Avonex prior to Tysabri is not a risk factor for PML.

[Myoak]

“Based on 68 out of 197 patients with PML as of 2-29-12”, Biogen published the following stats which can be found at


**URL removed by Moderator in compliance with MSWorld Guidelines. This may be put in your Profile for all registered, logged-in members to see. Go to UserCP > Edit Details**


under the heading “No Specific Pattern in Type of Prior IS (immunosuppressant) Use Identified in Patients with PML”.

Mitoxantrone 38
Azathioprine 11
Methotrexate 9
Cyclophosphamide 14
Mycophenolate 6
Other 8

Of course, these numbers total 86 so evidently someone transposed 6 and 8. In any case, the relevant point is that Biogen does not include interferon in their immunosuppressant list.

Special Kay, I don’t believe a patient who was on interferon alone could be considered in the same risk category with the listed immunosuppressants. Your neuro can tell you conclusively, but redwings was quite clear, also. Best Wishes!

[22cyclist]

Oh Boy! That was said much more simply and straightforward! Much easier than my explanation, thanks.

Most of us have taken the many, if not all of the immunomodulator shots (at least), before we go to Tysabri. In the U.S. anyway.

I have taken them all except Betaseron, had a short wash-out period due to low blood counts, but they bounced back, and I started no problem.

Good luck to you!

[Myoak]

I'm asking that the link I provided be restored to my post because it does NOT require membership to log on and read this information. All you have to do Seasha, or anyone, is scroll down once you click on the link to access this very important Biogen information for MS patients on Tysabri.

“Last edited by Seasha; 08-25-2012 at 09:50 PM.. Reason: url given requires membership to log on”

http://www.investorvillage.com/smbd....2048678&pt=msg

C’mon mods take a second to look, think, click and scroll. I would appreciate more than one moderator’s opinion on this if you continue believe it is a violation, Seasha. Thanks for everyone’s kind efforts!

I repeat... No membership is required to read the information.

[Seasha]

Hey Myoak! Today when I checked the url, it was fine! Yesterday when I checked it was a totally different page. Sorry for the confusion and NO! I wasn't implying that it was a violation.... the page just didn't have the same information and it didn't make any sense to viewers. Weird!

All is well that end well - right?

[ru4cats]

Wow! Awesome URL link! Thanks! My 1st post-Stratify II JC virus test done by Quest Labs will in late September, early October. So far 2 negatives....Hope I stay the same and don't seroconvert.

[Special Kay]

Wow! Such great responses on this thread!!

Thanks to all, especially RedWings and 22cyclist, for your posts, and to Myoak for that great link!

[Myoak]

Everything is well, Seasha.

Good information for MS patients should be downloaded or copied by them in case Biogen, or anyone else, has a magic wand which can make it disappear from public view. Generally, IMO, Biogen is fairly guarded about information they release for public viewing so I never hesitate to generate a copy when I can.

Occasionally, I have found posted information which was not intended for immediate public view removed from a website so doesn’t assume it will always be there. I can tell you from experience it may not be. If something is important to you, keep it, if at all possible.

Thank you for your James Wright quote and thank you for being a moderator, Seasha. All of us appreciate your work and that of the mods, a group of people who are using their talents to make the world a better place. You make our burdens lighter. Thanx to all the moderators.

O Seasha spring blossom most surely, you would know
The Branch Will Not Break and
Autumn Begins in Martins Ferry, Ohio

[Seasha]

O Seasha spring blossom most surely, you would know
The Branch Will Not Break and
Autumn Begins in Martins Ferry, Ohio

love that poet!


A Blessing
By James Wright
Just off the highway to Rochester, Minnesota,
Twilight bounds softly forth on the grass.
And the eyes of those two Indian ponies
Darken with kindness.
They have come gladly out of the willows
To welcome my friend and me.
We step over the barbed wire into the pasture
Where they have been grazing all day, alone.
They ripple tensely, they can hardly contain their happiness
That we have come.
They bow shyly as wet swans. They love each other.
There is no loneliness like theirs.
At home once more,
They begin munching the young tufts of spring in the darkness.
I would like to hold the slenderer one in my arms,
For she has walked over to me
And nuzzled my left hand.
She is black and white,
Her mane falls wild on her forehead,
And the light breeze moves me to caress her long ear
That is delicate as the skin over a girl’s wrist.
Suddenly I realize
That if I stepped out of my body I would break
Into blossom.


(Sorry to original poster - I couldn't resist)