Is Anyone Else Scared of Rituxan?

[Marky90]

As others have pointed out, there is no therapy for IgM deficiency. And given my health history since birth, I was more than likely born with the condition. For that reason, anything that could potentially trash my front line immunity is not of any interest to me.


My total IgG numbers are normal. Like most CFS folk, my IgG1 bounces up and down around the low normal border, but its companion, IgG3, is fine, along with IgG2 and IgG4. And for that reason, Medicare steadfastly refuses to give me IVIG therapy just to improve IgG1. And it's too expensive to pay out-of-pocket for it. Plus, my doc thinks it wouldn't help much since the IgG1 deficiency is so mild.

We need a double blind placebo ivig-study with strict canada-criteria,
The conflicting results atm are being misused by health departments and doctors
We are trying to get one going in Norway as we speak.

 

[Marky90]

YIKES!!

Speaking of enteroviruses… does anyone know what Dr. Chia's position is on Rituxan for CFS patients?

I have no idea. But given this paper, I'm guessing he wouldn't recommend it.

Its one case... And the details are beyond a pay wall..

 

[halcyon]

Its one case... And the details are beyond a pay wall..

There are at least 11 other reports in the literature of enteroviral infection complications with rituximab, 3 of them fatal.

 

[Marky90]

There are at least 11 other reports in the literature of enteroviral infection complications with rituximab, 3 of them fatal.

Right, I found this

Very nasty infections obviously

So one must decide for one self if youre willing to take the very slight risk of these complications

I would

Due to the large number of people who have been treated with ritux without these consequences

I suspect stem cell therapy (as some of the cases had endured) to heighten the risk for enterovirus infection, but thats an unscientific guess.

@Jonathan Edwards have you ever come across this or PML in your time? And would IVIG as a secondary treatment minimize the chances of these type of serious side effects?

 

[Marky90]

I found this new research on PML

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129694

The content is a bit over my head, but as i understand it they found a cytokine producing something that stops the JC-virus` genetic expression?

 

[Jonathan Edwards]

Right, I found this

Very nasty infections obviously

So one must decide for one self if youre willing to take the very slight risk of these complications

I would

Due to the large number of people who have been treated with ritux without these consequences

I suspect stem cell therapy (as some of the cases had endured) to heighten the risk for enterovirus infection, but thats an unscientific guess.

@Jonathan Edwards have you ever come across this or PML in your time?

Almost all of the cases of severe infection after rituximab are in people with other reasons for immunosuppression, as in lymphoma and in the case mentioned above, splenectomy, which in itself is a cause of fatal infections. PML and viral encephalitis have chiefly been reported in people who have at least one other major source of immunodeficiency. There are a very small number of cases where rituximab is the only recognisable rik factor, but then of course there are a tiny number of cases where no risk factor is known. I think the experience in RA is probably the most relevant in that serious infections of this sort are very rare despite the fact that RA itself does have a small impact in terms of immunosuppression in the sense of increased susceptibility to infection.

 

[halcyon]

I suspect stem cell therapy (as some of the cases had endured) to heighten the risk for enterovirus infection, but thats an unscientific guess.

The main (or maybe the only) risk with the enterovirus infections is probably hypogammaglobulinemia. I haven't looked at all the cases in the literature to see if any of the complicated infections occurred in absence of that. I recall Edwards saying that he never really saw hypogammaglobulinemia in his RA patients on rituximab, I assume due to the infusion dose and schedule being less hardcore than for cancer?

 

[Marky90]

Almost all of the cases of severe infection after rituximab are in people with other reasons for immunosuppression, as in lymphoma and in the case mentioned above, splenectomy, which in itself is a cause of fatal infections. PML and viral encephalitis have chiefly been reported in people who have at least one other major source of immunodeficiency. There are a very small number of cases where rituximab is the only recognisable rik factor, but then of course there are a tiny number of cases where no risk factor is known. I think the experience in RA is probably the most relevant in that serious infections of this sort are very rare despite the fact that RA itself does have a small impact in terms of immunosuppression in the sense of increased susceptibility to infection.

Thank you for your answer doctor., clarifying!

Lastly, could one make a case for the need of secondary immunoglobulin treatment, if one is treated with ritux, for e.g.4-5 years?

 

[halcyon]

Almost all of the cases of severe infection after rituximab are in people with other reasons for immunosuppression

Would preexisting low total or subclass IgG be a contraindication for rituximab use in non cancer patients? This is the main thing I worry about with indiscriminate use of rituximab in ME patients, some do have a measure of immune deficiency, though probably not as extreme as in lymphoma etc.

 

[out2lunch]

Would preexisting low total or subclass IgG be a contraindication for rituximab use in non cancer patients? This is the main thing I worry about with indiscriminate use of rituximab in ME patients, some do have a measure of immune deficiency, though probably not as extreme as in lymphoma etc.

But here's the thing. Aren't we as ME patients at risk for lymphoma, anyway? I seem to recall that statistically, cancer is the number one cause of death in ME, with lymphoma being the number one cancer.

Where do you draw the line between benefit and risk taking?

If you knew ahead of time that you had problems with immunosuppression like I do, and you also knew that lymphoma risk was greater for you than the general population, even just slightly… would you still take the drug?

Maybe I'm being too paranoid, but no way I would take it.

My life with ME sucks but at least I'm not immediately dying from it.

 

[leokitten]

Would preexisting low total or subclass IgG be a contraindication for rituximab use in non cancer patients? This is the main thing I worry about with indiscriminate use of rituximab in ME patients, some do have a measure of immune deficiency, though probably not as extreme as in lymphoma etc.

Yes, @Jonathan Edwards mentioned in other threads that below normal IgG levels is contraindicated for rituximab therapy.

 

[Jonathan Edwards]

Thank you for your answer doctor., clarifying!

Lastly, could one make a case for the need of secondary immunoglobulin treatment, if one is treated with ritux, for e.g.4-5 years?

Most people treated with rituximab for autoimmunity do not become hypogammaglobulinaemic so it is unnecessary.

 

[Jonathan Edwards]

Would preexisting low total or subclass IgG be a contraindication for rituximab use in non cancer patients? This is the main thing I worry about with indiscriminate use of rituximab in ME patients, some do have a measure of immune deficiency, though probably not as extreme as in lymphoma etc.

A significantly low IgG would be a contra-indication for rituximab but I doubt that occurs in many PWME. Borderline levels are not a problem. As far as i can judge the evidence for significant immune deficiency in ME is still very uncertain. The main evidence is for NK cell function and that has not been consistently replicated and nobody really knows whether it is clinically relevant anyway.

 

[Marky90]

Almost all of the cases of severe infection after rituximab are in people with other reasons for immunosuppression, as in lymphoma and in the case mentioned above, splenectomy, which in itself is a cause of fatal infections. PML and viral encephalitis have chiefly been reported in people who have at least one other major source of immunodeficiency. There are a very small number of cases where rituximab is the only recognisable rik factor, but then of course there are a tiny number of cases where no risk factor is known. I think the experience in RA is probably the most relevant in that serious infections of this sort are very rare despite the fact that RA itself does have a small impact in terms of immunosuppression in the sense of increased susceptibility to infection.

Here are some numbers for PML with regards to RA, in other words you seem to be spot on!

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428054/


"Results
Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease."

"
Conclusion
These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low."

 

[SaraEngland]

@Jonathan Edwards, would a combination of IM immunoglobulin and RTX be subject to any problems? There are several reports of benefit from 5ml Gammanorm weekly in Sweden/Norway. Maybe it could speed up remission in combination with anti CD20?

 

[leokitten]

New paper from Lipkin et al.

Fatal Coxsackie meningoencephalitis in a patient with B-cell lymphopenia and hypogammaglobulinemia following rituximab therapy.
Palacios T1, Bartelt L2, Scheld W2, Lopes MB3, Kelting SM3, Holland S4, Lipkin WI5, Quan PL5, Borish L6, Lawrence M7.

@halcyon, @Marky90, others attached is the full article

 

[halcyon]

@halcyon, @Marky90, others attached is the full article

Thank you leo, that was interesting. They don't state explicitly at what age she was given the rituximab, it seems like there was quite a time lag between the rituximab treatment and the enterovirus infection, though it sounds like they don't know exactly when the hypogammaglobulinemia began. In spite of that, it is their hypothesis that the rituximab caused profound B cell lymphopenia and secondary hypogammaglobulinemia.They included this bit of what seems like prudent advice:

Routinely obtaining immunoglobulin levels and peripheral
B-cell numbers before and after rituximab treatment should be
considered to monitor for pre-existing and secondary immunodeficiency.
Prompt immunoglobulin replacement intravenously
or intrathecally should be initiated in patients with persistent
B-cell absence because this might avert severe EM infections in
these high-risk patients. As the present case illustrates, immunoglobulin
replacement might be inadequate salvage therapy in
established EM.

This case also illustrates an important point that I've seen illustrated in other cases. Despite the fact that this patient was killed by a disseminated enterovirus infection in her brain, she had two CSF tests that were completely negative for enterovirus. It was only a brain biopsy and then post-mortem PCR test of tissue that allowed them to see the infection. This shows that we need to be extremely cautious about proclaiming no viral involvement in diseases like ME based solely on blood/CSF testing.

 

[Bob]

Despite the fact that this patient was killed by a disseminated enterovirus infection in her brain, she had two CSF tests that were completely negative for enterovirus. It was only a brain biopsy and then post-mortem PCR test of tissue that allowed them to see the infection.

Interesting observation!

It says that "repeat CSF studies, including EV polymerase chain reaction (PCR), were negative".

It goes on to say that, after these initial negative tests, and while the patient was in hospital, a further brain biopsy, and the previous negative CSF samples, were sent to the CDC who detected enterovirus (it doesn't say if they determined the exact virus, or if they had a positive reading in the CSF samples):

Given the lack of clinical improvement despite appropriate medical therapy, a repeat brain biopsy examination was performed. In addition, tissues from the first brain biopsy and CSF were sent to the Centers for Disease Control and Prevention for immunohistochemistry and PCR for Toxoplasma species, Mycoplasma species, EV, Japanese encephalitis, and flaviviruses. Results were positive for EV by immunohistochemistry and PCR.

It seems to be only after death that the exact cause was determined.

Source:
http://forums.phoenixrising.me/inde...e-scared-of-rituxan.37697/page-14#post-607613

 

[Bob]

Fatal Coxsackie meningoencephalitis in a patient with B-cell lymphopenia and hypogammaglobulinemia following rituximab therapy.
http://forums.phoenixrising.me/inde...e-scared-of-rituxan.37697/page-14#post-607613

A few extra-ordinary things need to be noted about this case.

Firstly, the patient had an autoimmune disease of the blood. I don't know if this is relevant, but it a specific circumstance.

Secondly, and I don't know if this would make any difference, but the patient was given many doses of Rituximab (8 doses during a 10 month period):

Then, she received high-dose (1 mg/kg) IVIG and a total of 8 doses of 375 mg/m2 of rituximab during a 10-month period for severe idiopathic thrombocytopenic purpura.

Also, Rituximab wasn't the only treatment received:

She was initially treated with danazol and corticosteroids.
[...]
At 23 years, she received pneumococcal and meningococcal vaccines and underwent splenectomy for refractory idiopathic thrombocytopenic purpura.

But, most notably, it was after the age of 15 (exact timing isn't specified) that she received Ritiximab, after which "she did well until 27 years of age". It was age 27 years, 12 years after the Riuximab, that she was hospitalised.

By this time, she had developed "marked hypogammaglobulinemia with impaired antibody response and profound B-cell lymphopenia."

If there was an issue with B-cells 12 years after treatment with Rituximab, this raises the question of whether there may have been a deeper and complex underlying immunological issue causing problems, rather than a simple adverse reaction to Rituximab. The B-cell lymphopenia may have been a complication of the Rituximab, but it may have happened roughly 12 years after the infusions, as far as I can work out; The paper doesn't indicate whether her B-cell levels ever returned to normal after the Rituximab, but her clinicians had roughly 12 years during which they could have checked and addressed the issue of B-cells and antibody response not returning to normal.

Is it normal not to check that B-cell levels are returning to normal, after treatment with Rituximab? And to monitor for other blood counts?

 

[Jonathan Edwards]

@Jonathan Edwards, would a combination of IM immunoglobulin and RTX be subject to any problems? There are several reports of benefit from 5ml Gammanorm weekly in Sweden/Norway. Maybe it could speed up remission in combination with anti CD20?

Giving Immunoglobulin as well as rituximab would be very expensive and I would not mix the two until we have clear evidence that rituximab actually works - or indeed that immunoglobulin works. IM and IV immunoglobulin should have much the same effect.