immune compromised?

Gilenya, or Fingolimod, is the first approved oral disease modifying drug for MS.

immune compromised?

Postby mmpetunia » Sat Aug 10, 2013 6:00 pm

i was reading about the mechanism by which gilenya works-- trapping white blood cells in the lymph nodes. also that gilenya reduces your ability to fight infections... does this mean that if i take gilenya i am immune compromised? has anyone had a problem with infections, colds, or viruses increasing after taking gilenya?
Dx: 9/8/11 RRMS
OMS diet plus lean poultry
Tecfidera as of 8/21/2014
18+ brain lesions and 6 spinal lesions
EDSS 1.5-2
http://mylaceybrain.wordpress.com
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Re: immune compromised?

Postby CaliReader » Sat Aug 10, 2013 7:58 pm

Hi Mmpetunia,

I wasn't able to find the FDA data describing the clinical trial results that I read before going on Gilenya. But here are two sources you might find useful. The claim is that some but not all aspects are suppressed and that immune surveillance is retained.

Good luck. Whatever you decide.

Excerpt from full text available journal article re study results

Full text available pubmed central
Discov Med. Author manuscript; available in PMC 2013 June 27.
Published in final edited form as:
Discov Med. 2011 September; 12(64): 213–228.
PMCID: PMC3694567
NIHMSID: NIHMS474753
A Mechanistically Novel, First Oral Therapy for Multiple Sclerosis: The Development of Fingolimod (FTY720, Gilenya)
Jerold Chun, M.D., Ph.D. and Volker Brinkmann, Ph.D.


Fingolimod Immunological Activities
*****
Two corollaries with particular relevance to MS through this differential effect of fingolimod on CCR7-positive
vs. CCR7-negative T cells may contribute to efficacy and safety, respectively. First, fingolimod may produce efficacy
by sequestering the CCR7-positive cells, which include naïve and central memory T cells,
the latter of which have a key role in immunological memory. Following antigen exposure,
central memory T lymphocytes can undergo clonal expansion and differentiation to generate
effectors/effector memory T cells which provide adaptive immunity against recognized antigens
(Iezzi et al., 2001; Sallusto et al., 2004). Central memory T cell retention by fingolimod
could function as a therapy in MS since more than 90% of T cells that are found in the cerebrospinal fluid (CSF)
appear to be of the central memory subset (Kivisakk et al., 2004).
The contained autoreactive, pathological T cells could therefore be prevented from entering the CNS
by fingolimod sequestration, thereby abrogating their differentiation into pathological effectors and
effector memory T cells upon interaction with CNS-resident antigen-presenting dendritic cells.
In animal models, fingolimod prevented accumulation of pathological Th17 cells in the nervous system
(Zhang et al., 2008; 2009), supporting Th17 cell- or Th17 cell precursor sequestration as an efficacy mechanism.
Accordingly, phenotypic Th17 cells were reduced in the circulation in fingolimod-treated MS patients
(Mehling et al., 2010). In addition to efficacy by CCR7-positive cell sequestration of pathological T cells,
fingolimod could provide safety through maintained immunosurveillance. Such functionality would be
produced by preferentially not affecting CCR7-negative effector memory T cells of any functional phenotypes

In support of the above, another study proposed that Gαi2 null T cells egress independent of S1P-mediated chemotaxis
(Zhi et al., 2011), and these cells were also not retained by fingolimod. Intravital imaging of lymph nodes revealed
that T cells approach and engage cortical sinusoids in lymph nodes similarly in the presence or absence of fingolimod.
However, after engagement of the sinus, most T cells retract and migrate back into the parenchyma in fingolimod-treated
animals, due to a failure of the cells to establish adhesion on the sinus, whereas Gαi2-deficient T cells adhere firmly
on the sinus, which prevents their retraction, facilitating their transmigration of the lymphatic endothelial barrier.
Interestingly, Gαi2-deficient T lymphocytes are hyper-responsive for T cell receptor signaling and cytokine production,
with a relaxed costimulatory requirement (Huang et al., 2003) — a phenotype matching effector memory T cells — again
supporting sparing of this subset by fingolimod.

****

Immunomodulatory Approaches to MS Therapy
A notable corollary of the dual immunological and CNS fingolimod mechanisms is that fingolimod does not fit
the profile of an immunosuppressive agent like those in common use in the transplantation field - e.g.,
“classical” immunosuppressive agents like calcineurin inhibitors [Cyclosporine, Tacrolimus
(Borel and Kis, 1991; Juhasz et al., 2009; Stahelin, 1996)], high dose corticosteroids [e.g., Prednisone (Goetzl, 2008)]
, and cytotoxic and/or antimitotic agents [azathioprine, mycophenolate, or cladribine (Goetzl, 2008; Neuhaus et al., 2007)]
or biologicals, including a growing number of humanized antibodies raised against immune cell targets [CD3, IL-2 receptor,
integrins, CD52 (Buttmann, 2010; Nitta et al., 1992; Steinman, 2005; Wolff et al., 2004)].
Early approaches to the treatment of MS utilized classical immunosuppressive strategies, some of which continue to be used
today (Neuhaus et al., 2007). However, risk of serious neoplastic and/or infectious adverse events limits their use.
This issue has been underscored by the rare occurrence of progressive multifocal leukoencephalopathy (PML) associated
with the use of natalizumab or rituximab (Buttmann, 2010). T cell immunosuppression may be involved in both cases;
in addition to its effects on T cell trafficking, natalizumab may interfere with the VLA4-VCAM1 costimulatory pathway
that is critical to human CD4 T cell proliferation (Weitz-Schmidt et al., 2001), and therapeutic B cell depletion by
rituximab was shown to impair B cell antigen-presentation and, as a consequence, CD4 T cell activation and clonal expansion
in response to pathogen challenge (Bouaziz et al., 2007). Therefore, the sparing of effector memory T cells in both CD4
and CD8 populations by fingolimod could be critical to immunosurveillance; in the meninges of mice, fingolimod
preferentially reduced naive and central memory T cells, whereas anti-VLA4 treatment primarily depleted the effector
memory population (Derecki et al., 2010) (see also above for the key role of circulating central memory T cells in
pathology of MS).
****
The above data support the notion that fingolimod at its approved dose may not act as a potent immunosuppressant:
1) CNS effects are unrelated to immunosuppression; 2) suboptimal prevention of graft rejection was achieved
in renal transplantation studies in combination with cyclosporine, despite being at 10X the approved MS dose;
3) immunological constituents are maintained (cellular and humoral), with reversible effects on cell location of some
(but not all) lymphocyte subsets —without inhibition of proliferation, differentiation, and cytotoxicity;
4) immunological surveillance is maintained through relatively unaffected effector memory T-cells; and
5) clinically, the overall incidence of infections as well as of serious and severe infections was not
increased over placebo control in the FREEDOMS trial in phase III studies. Overall, the emerging picture
identifies S1P receptor pathways in MS that can provide efficacy through mechanisms different from classical
immunosuppressants

****
Collectively, the data show that activation and proliferation of naïve and central memory T-cells, as well as
differentiation and trafficking of effector memory T-cells, may not be significantly affected by fingolimod,
thereby preserving this arm of the adaptive immune system that can reduce the risk of infection and cancers
common with immunosuppressive agents. Consistent with this mechanism, the combined data from both
aforementioned Phase III trials did not suggest an increased incidence of either infections or malignancies
associated with fingolimod treatment (Cohen et al., 2010; Kappos et al., 2010).
(Mehling et al., 2008), which may leave lymph nodes, independent of S1P1 signaling (Pham et al., 2008).



Excerpt from Health Canada
http://www.hc-sc.gc.ca/dhp-mps/prodphar ... 16-eng.php
Health Canada Summary Basis of Decision (SBD) for PrGILENYA*

Gilenya* induced a rapid decline in peripheral blood lymphocyte counts within the first few hours of dose administration,
with counts reduced to 50% of the baseline values after 8 hours. With chronic daily dosing lymphocyte counts continued
to decrease over the first two weeks and reached a low point (~0.5 x 109/L) that is approximately 30% of baseline values.
In the clinical studies, lymphocyte counts below 0.2 x 109/L were considered clinically notable values, for which
treatment interruption was to be considered. These values were reached at least once in the two-year study (D2301)
by 18% of patients administered 0.5 mg Gilenya* and 4% of patients administered 0.5 mg Gilenya* had lymphocyte counts
below 0.2 x 109/L for at least 180 days. A complete blood cell count should be obtained before initiating treatment
to ensure a patient is not lymphopenic, and may be checked during an active infection. Recovery of lymphocyte counts
to baseline levels typically takes approximately two months following treatment discontinuation, during which time
the immune effects may still be present and the patient at an increased risk for infections. During this time,
initiating treatment with other immunosuppressive therapies would warrant extreme caution.
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Re: immune compromised?

Postby CaliReader » Sat Aug 10, 2013 8:00 pm

And yes... re your second question, since starting this drug I have had one UTI and a mild chest infection and a short lived ear ache.
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Re: immune compromised?

Postby CureOrBust » Sat Aug 10, 2013 8:30 pm

mmpetunia wrote:...also that gilenya reduces your ability to fight infections... does this mean that if i take gilenya i am immune compromised? has anyone had a problem with infections, colds, or viruses increasing after taking gilenya?

I am on Gylenia, and what you asked was my BIGGEST concern on starting it, as a cold/flu was my biggest trigger for a relapse. However, I have not had a cold/flu for about a year before starting Gylenia, and I haven't had one since starting Gylenia.

I *think* I may of noticed a little phlemmy-mucossy-chesty feeling when I first started Gylenia, but it was minor and hard to pin down as a cause of Gylenia.

As a cold/flu is trigger for a relapse, I keep a bottle of Amantadine handy if anyone sneezes near me on the train to work. I know its fairly useless against most common virus, but it doesn't hurt either. I also have Tamiflu handy, but I haven't had to use it for some time; It may of actually passed its expiry date....

Hope this helps.
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Re: immune compromised?

Postby Ladymac » Sun Aug 11, 2013 4:44 am

Good morning cureorbust and mmpetunia,

It is my experience that MS is an autoimmune disease. I know that when it is cold, flu, etc., season I stay away from everyone as much as I can and am OCD about using PURELL on my hands if I touch anything, before I eat, and take special care when opening doors, etc., in public. With said, I had a conversation with several others with MS about this and we all agree that the most Germ infected places to be are Doctors Offices/Hospitals and the Airport/Plane (and I bet on a train too). Some times we also don't realize that our computers need to be dissenfected, phones (including cell phones), our keys, pocket books and our steering wheels and inside car handles and shifts because we can pick up something in a store and transfer it onto something we use a lot and get sick.

Now that sounds crazy OCD, but as long as we are conscious of that regardless of our meds that can reduce our ability to fight, so does Solumedrol when we have an exacerbation because we are not fighting, the steroid is. So it's a vicious circle. My Lymphocytes have dropped quite a bit in 4 months being on Tecfidera, but I am still in the normal range with no concern by my MS Specialists, but we are testing me every 4 weeks now.

One thing that I do know is that when the Flu shots come out, my Docs say I must get it (not the nasal one, must be shot) and to get it early so that I don't wait until I have the flu.

Glad to Hear that you are doing great on Gylenia and your answers to mmpetunia were spot on.
Blessings,

Ladymac
RRMS diagnosed 2006
Tecfidera Started April 2013
:)
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Re: immune compromised?

Postby sruasonid » Sun Sep 08, 2013 12:33 pm

I've been on Gilenya for over 18 months now. About 8 months ago I started getting HORRIBLE herpes outbreaks. I contracted herpes in 77 but had not had a single outbreak since 1988 and only 3 or 4 mild ones between 77 and 88. Early this year (2013) after about a year on Gilenya, I got the first outbreak of herpes I'd had in 25 years. It was worse than the first one and lasted over 2 weeks. It was gone for maybe 3 days and the next one hit. Since then I've had them nonstop even though my OB/GYN put me on a high dose of Valtrex that I take every day. About the same time I got a bladder infection; same thing, after being treated for it and it went away, I kept getting another and another no matter what antibiotic I take. Two months ago I developed a chronic cough. At first it was just annoying, but now it feels like I have cement in my chest and I can't cough it up. It keeps me awake at night. I don't know if that's considered an infection but it's there. My blood pressure has gone up steadily every month since starting Gilenya (BP readings taken by my internist NOT the neurologist who only sees me for 60-90 seconds and ignores anything I say, never takes blood pressure readings or any kind of tests, and poo-poohs any concerns because "you're not half as bad off as my other patients - you're not even in a wheelchair yet. It could be a lot worse.") Last reading was 204/107; it hasn't been below 160/90 for a year now and goes up every month. Last Thanksgiving week I had a "mild" stroke (it doesn't feel "mild" when it happens to you). I've been feeling sicker and sicker, and my MS symptoms have gotten much, much worse than when I was diagnosed in 2011, but the neuro says I'm "getting better" when he sees me for that 90 seconds and has me squeeze his fingers. Never mind I can't hold onto anything without dropping it, turn a key in a lock, drive, see, stand up or walk without falling, stay awake/alert more than 1-3 hours a day, feel my legs or feet below the knee or either hand, or remember anything or follow a conversation. I'm looking for a new neurologist because he will not take me off Gileya as he believes it will "reverse" the MS damage. I stopped taking it myself this morning and I'll never, ever take it again. Ever. Just my own personal experience, not giving a medical opinion or making any claims or connections. This is just what happened to me.
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