Myasthenia gravis Rituximab trial in US

[Hutan]

Maybe the fact that the National Institute of Neurological Disorders and Stroke is doing this type of study might make them more excited to accept ME into their fold.

http://www.ninds.nih.gov/disorders/clinical_trials/NCT02110706.htm

A Phase II Trial of Rituximab in Myasthenia Gravis

The National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, is looking for individuals to participate in clinical studies.

Description:
The purpose of this trial is to learn if rituximab is a safe and effective drug for people with myasthenia gravis (MG). This trial also will determine if rituximab will allow people with MG to decrease their prednisone dosage or discontinue prednisone treatment.

MG is a chronic autoimmune, neurological disorder of neuromuscular transmission. Although there is no known cure, effective treatments can help people with the disorder lead full lives. MG often is treated with prednisone, a medication that suppresses the immune system. However, prednisone, often only partially controls the disease and can have serious side effects when used for long periods of time. Rituximab is a type of medicine known as monoclonal antibody (MAB) and works by decreasing certain white blood cells—called B cells—that are believed to produce a reaction that leads to MG.

This randomized, placebo-controlled trial is coordinated by NeuroNEXT (the NIH Network for Excellence in Neuroscience Clinical Trials). It will determine the safety, tolerability, and benefit of rituximab in people with MG. Fifty people will enroll in this trial at NeuroNEXT clinical study sites across the U.S. Participants will receive either rituximab or a placebo (an inactive substance) administered in two 4-week cycles. The cycles will be separated by 6 months. Participants will have regular study visits every 4 weeks which will include MG-focused physical examinations, blood draws, and questionnaires. The trial also will examine immunological changes that may occur during treatment in an effort to help develop future patient-tailored therapies.

Study duration for participants is about 52 weeks. The study drug is being provided by Genentech.

Study Design:
Interventional
Study Locations:
Multiple U.S. locations
For more information:
Contact: Hong Vu, telephone: 1-844-MGStudy or email MGStudy@yale.edu; or visit: https://clinicaltrials.gov/ct2/show/NCT02110706, or https://www.neuronext.org/nn103-rituximab-mg

Last Reviewed March 12, 2015​

 

[anciendaze]

I want to point out that myasthenia gravis is firmly in the category of autoimmune disorders. There are detectable antibodies to acetylcholine receptors in many patients, and antibodies to specific receptors for tyrosine kinase, MuSK, in others. Both classes of receptors are associated with neuromuscular junctions.

Why these antibodies are present is another question. They could be the ultimate cause, or they could be a response to an earlier defect associated with those receptors which is harder to identify. In that second category I'm thinking of Schwann cells missing signals which normally keep them out of neuromuscular junctions and destroying the synapse. In that case the autoantibodies would be largely a consequence of pathology.

 

[Marky90]

Great to see.

I suspect there is so many conditions that are probably autoimmune of some sort, which would benefit fromRitux or biosimilars..

 

[Hutan]

Myasthenia Gravis May Follow Infection by West Nile Virus
July 02, 2013

http://www.medscape.com/viewarticle/807230

West Nile virus infection (WNV) is now linked to the development of myasthenia gravis (MG) some months later, a series of case reports indicates.

....explained that WNV is an RNA neurotropic arthropod-borne flavivirus that can cause neuroinvasive disease manifesting as meningitis, encephalitis, or poliomyelitis.

There is no evidence that the virus directly damages the neuromuscular junction, suggesting that host factors are involved in the development of MG, Dr. Leis noted.

At this meeting, he reported on 6 cases of MG, all with similar features, that developed 3 to 7 months after acute infection with WNV and after initial neurologic deficits had stabilized....None of the patients had any evidence of MG before the WNV infection.

"I would suspect...that the virus shares proteins that are also present in the [acetylcholine] receptor and then you generate the immune response against the virus and there's cross-reactivity to an antigen that's present in the body," he commented to Medscape Medical News. "A second possibility would be that something changes within the thymus because acetylcholine receptors are expressed within the thymus, and the thymus is important for the genesis of myasthenia gravis."

He said the clinical message is to be aware of the possibility of MG if a patient has secondary weakness. "Usually the patients get better, and when you are facing secondary problems in terms of fatigue, muscle weakness you should think of myasthenia. ... You have to recognize that something new occurred.

Dr. Stoll said the term poliomyelitis relates to a clinical picture that does not have to be caused by the typical enteric polio virus. It describes a condition in which an infectious agent or an immune attack destroy anterior horn cells.

Dr. Leis noted that he is seeing more cases of WNV and predicts an increasing number as time goes on. So far, he has .... just received 3 more case referrals of MG from colleagues, for a total of 9. He has published this work in an article online in Muscle & Nerve, and it will later appear in print.​

 

[Hutan]

Myasthenia gravis: A comprehensive review of immune dysregulation and etiological mechanisms
in the Journal of Autoimmunity 2013

This is a helpful overview paper.
http://dosequis.colorado.edu/Courses/BrainWeb/papers/MG1.pdf

After a triggering event, such as viral infection, in a genetically favorable background, thymic epithelial cells (TEC) overproduce IL-1, IL-6, and IFN-b and lymphocytes overproduce TNF-a and IFN-g. These cytokines increase the expression of MHC class II, AChR, and the chemokines CXCL13, CCL21, and SDF-1 (not represented in the model), which contribute to the attraction of B cells from the periphery. Estrogens promote the proliferation of B cells, which could explain why follicles are primarily found in females. This inflammatory milieu modulates the T cell phenotype: Treg cells produce Th17 cytokines, and both Tconv and Treg cells produce IFN-g, TNF-a, and IL-21. IL-17 and IL-21 favor the development of T follicular helper cells (Tfh) and the generation of germinal centers. In this inflammatory environment, the Treg cells become inefficient, and the Tconv become resistant to suppression. Altogether, this cascade of events leads to thymic hyperplasia and MG. ​

Consideration is given to the idea of a viral cause of MG.

An antiviral signature can be observed in the MG thymus. Numerous IFN-I-induced genes are overexpressed in the thymuses of MG patients [58,130]. The MG thymus also exhibits over- expression of IFN-b and TLR4 [131], as well as double-stranded (ds) RNA signaling molecules, including TLR3, protein kinase R, IFN- regulatory Factor (IRF)5 and IRF7. Recently, Poly(I:C), a synthetic analog of dsRNA, was demonstrated to specifically induce thymic overexpression of a-AChR. ​

Because anti-AChR antibodies are both highly specific for MG and pathogenic, the activation of dsRNA signaling could contribute to the etiology of MG [132]. dsRNA is the genetic material of certain viruses, and it is also produced during the replication cycle of many viruses. Thus, these data strongly suggest that MG develops after viral infection.

This observation could also be related to the presence of EBV-positive cells in the MG thymus [133]. EBV encodes small RNAs (EBER) that trigger TLR3 signaling and induce IFN-I and pro-inflammatory cytokine expression, similarly to Poly(I:C) [134]. In addition, a recent study reported higher levels of antibodies against the type 1 nuclear antigen of EBV in the serum of EOMG patients than in healthy controls ​

 

[leokitten]

Myasthenia Gravis May Follow Infection by West Nile Virus
July 02, 2013

http://www.medscape.com/viewarticle/807230

West Nile virus infection (WNV) is now linked to the development of myasthenia gravis (MG) some months later, a series of case reports indicates.​

Yet more evidence that infection can trigger autoimmunity. Ebola is also doing this i.e. post-Ebola syndrome. The research community really must start investigating autoimmunity as a cause or major driver of ME/CFS instead of spending zero resources on this hypothesis and all resources on other hypotheses that study potential causes or aspects of the disease that won't result in treatments for another 10-20 years. We cannot afford to wait that long.

 

[Snow Leopard]

Very interesting, I hope this trial of Rituximab in Myasthenia Gravis is successful!

 

[leokitten]

Yet more evidence that infection can trigger autoimmunity. Ebola is also doing this i.e. post-Ebola syndrome. The research community really must start investigating autoimmunity as a cause or major driver of ME/CFS instead of spending zero resources on this hypothesis and all resources on other hypotheses that study potential causes or aspects of the disease that won't result in treatments for another 10-20 years. We cannot afford to wait that long.

Forgot to mention in addition to post-Ebola syndrome (PEVDS) and post-polio syndrome there is also post-sepsis syndrome, they all basically have the same symptoms and they all are strikingly similar to ME/CFS.

I don't understand how the medical and scientific community after all these years haven't noticed how these diseases are essentially the same.

 

[Kati]

Forgot to mention in addition to post-Ebola syndrome (PEVDS) and post-polio syndrome there is also post-sepsis syndrome, they all basically have the same symptoms and they all are strikingly similar to ME/CFS.

I don't understand how the medical and scientific community after all these years haven't noticed how these diseases are essentially the same.

@leokitten the message is not going through. So much stigma for this disease, and cyet there would be much interest for post ebola syndrome, because it's exotic, seemingly a threat for the US should an outbreak happens on homeland, and it's new.

On a side note, did you ever hear from your boss following your letter? Seemingly he doesn't seem to fond of ME.