NYT: Dr ill with rare immune disease discovers treatment

[edawg81]

His Doctors Were Stumped. Then He Took Over.

https://nyti.ms/2kzaTet


Dr with rare castleman disease (immune) finds his own treatment, when no one else could.


Some similar symptoms to CFS ME. Can any technical people comment about possible applications / relationship of MTOR treatment in ME? Anyone have any thoughts on this? Please tag any technical people that can give expert input. @Hip @Jonathan Edwards

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Exerpt below:

After a round of chemotherapy, he improved enough to be discharged and started looking into what secrets the tests might reveal. It turned out that five months before he started noticing symptoms in December, his T cells — one of the key weapons in the body’s immune arsenal — had starting activating, preparing for a fight even though there was no apparent threat. Then, about three months before his relapse, he noticed that he had started producing more VEGF, a protein that instructs the body to make more blood vessels, and is another sign of an immune system gearing up.

These two hints gave him an idea: Maybe the problem was with one of the body’s communication lines, the one that triggered production of VEGF and also told the T cells to begin activating. If Dr. Fajgenbaum could get his body to shut down that communication line — known as the mTOR pathway — he might be able to stop his immune system from overreacting and prevent a relapse.

The discovery was exhilarating. “I felt like I was part of steering the ship,” Dr. Fajgenbaum said. “This time I was part of this team.”

With this major clue in hand, he and his doctors turned to potential treatments, existing drugs that were known to shut down the mTOR pathway. The one that seemed the best option was practically hiding in plain sight. Sirolimus, also known as Rapamune, was commonly given to kidney transplant patients to prevent their bodies from rejecting the organ. The drug had been on the market for years and was known to have few serious side effects.

 

[Hip]

@nandixon, this mTOR pathway question may be of interest to you.

Can any technical people comment about possible applications / relationship of MTOR treatment in ME?

Nandixon has a theory that ME/CFS might benefit from boosting mTOR — the opposite of the way Dr Fajgenbaum treated his Castleman disease, which was to suppress mTOR using the drug rapamycin (sirolimus).

 

[xrayspex]

curious if you think Castleman had an abnormal ESR or C Reactive Protein---mine are always normal on regular bloodworkup. The only way I found out I had autoimmune Sjogrens is we did specific antibody test. The reason I ask is I am wondering for a person who doesn't have access to labs like this doc did but had normal routine blood workup how they could get their physician to try a treatment like this.

 

[edawg81]

Several of the discussed treatments treatments for Castleman disease per wikipedia seem to mirror some treatments discussed on this forum, just goes to show you that immune disfunction is truly a spectrum of illnesses.

There is no standard therapy for multicentric Castleman disease. Treatment modalities change based on HHV-8 status, so it is essential to determine HHV-8 status before beginning treatment. For HHV-8-associated MCD the following treatments have been used: rituximab, antivirals such as ganciclovir, and chemotherapy.[11]

For HHV-8-negative MCD (idiopathic MCD), the following treatments have been used: corticosteroids, rituximab, monoclonal antibodies against IL-6 such as tocilizumab and Siltuximab, and the immunomodulatorthalidomide.[12]

Siltuximab (Sylvant), a monoclonal antibody that binds interleukin-6, preventing it from binding to the IL-6 receptor, was approved by the U.S. Food and Drug Administration for the treatment of multicentric Castleman disease on April 23, 2014.[13][14] Preliminary data suggest that treatment siltuximab may achieve tumour and symptomatic response in 34% of patients with MCD.[15]​

 

[nandixon]

Nandixon has a theory that ME/CFS might benefit from boosting mTOR — the opposite of the way Dr Fajgenbaum treated his Castleman disease, which was to suppress mTOR using the drug rapamycin (sirolimus).

Yes, most other types of diseases (autoimmune, cancer, neurodegenerative, metabolic) often have an over-activated mTOR (mTORC1) pathway. That seems to be the case in Castleman disease as well.

In ME/CFS, the mTORC1 pathway, and particularly beginning at the level of the enzyme known as Akt (i.e., the Akt/mTORC1 pathway) appears to be under-activated. Other illnesses with an under-activated mTORC1 include SIRS/sepsis and starvation, both of which ME/CFS seems to resemble more than other diseases.

On a broader level, I think that most of the pathways and metabolic processes which involve signaling by sphingosine-1-phosphate (S1P) are under-activated in ME/CFS, including those involving endothelial function, blood pressure/volume regulation, etc.

The Akt/mTOR pathway is just one of those S1P-related pathways. But it's perhaps the most important, though, because it leads to the pyruvate dehydrogenase (PDH) complex and is therefore a critical energy-producing pathway. The recent Fluge & Mella study found the PDH complex to be impaired in ME/CFS.

Additionally, because the PDH complex produces acetyl-CoA, and since aetyl-CoA is necessary to make palmitoyl-CoA, which is the starting material (together with serine) for the de novo synthesis of ceramides in the body, this makes the PDH complex simultaneously both downstream and upstream of what appears to be impaired S1P signaling in ME/CFS (because S1P is made from ceramides).

Anyway, under the model above, using the drug rapamycin (a potent mTOR inhibitor) that the Castleman patient found effective for his disease would theoretically be one of the worst possible drugs to use in ME/CFS.

 

[edawg81]

Just an FYI, Cort has now chimed in on this article via his blog:

http://www.healthrising.org/blog/20...ugh-chronic-fatigue-fibromyalgia-way-forward/