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CRPS with dysautonomia patient treated with plasma exchange and rituximab

voner

Senior Member
Messages
592
http://www.ncbi.nlm.nih.gov/pubmed/26011726

Complex Regional Pain Syndrome and Dysautonomia in a 14-Year-Old Girl Responsive to Therapeutic Plasma Exchange

Reflex sympathetic dystrophy, also known as complex regional pain syndrome (CRPS), has recently been shown to be associated with autoantibodies against b2-adrenergic and muscarinic M2 receptors. In addition to pain and sudo- motor/vasomotor symptoms, dysautonomia is also observed in a subset of CRPS patients. Despite its severity, there are few effective therapies for CRPS described to date. We report a case of a 14-year-old girl with CRPS of her right leg and dysautonomia (gastroparesis, postural tachycardia) refractory to multiple therapies, successfully treated with therapeutic plasma exchange (TPE) with albumin replacement. The patient, who has serum anti b2- adrenergic and muscarinic M2 receptor autoantibodies in addition to nicotinic acetylcholine receptor ganglionic autoantibodies, underwent an initial course of five TPEs over a 2-week period. She demonstrated a clinical response to TPE as manifested by a rapid improvement in her fatigue and gastroparesis, with a gradual yet significant improvement in her leg pain and sudomotor/vasomotor flares. Following the loading procedures, the patient was treated with rituximab. She continues to require periodic TPE to maintain a remission, with additional immunosup- pression being considered long term. Although further studies are needed, TPE (in combination with immunosup- pression) may be an appropriate therapy for CRPS patients with detectable autoantibodies, as it is for better characterized diseases with autoantibodies against neuronal surface receptors such as myasthenia gravis or Lambert C 2015 Wiley Periodicals, Inc. Eaton myasthenic syndrome. J. Clin. Apheresis 00:000–000, 2015

I did not know These auto antibody tests existed.

......Given worsening dysautonomic symptoms, the patient’s serum was sent to Mayo Medical Laboratories (Rochester, MN) for an Autoimmune Dysautonomia evaluation. The testing revealed an acetylcholine receptor ganglionic neuronal antibody (0.08 nmol/L; refer- ence value 0.02).

Serum was also sent to Berlin Cures GmbH (Berlin, Germany), and........ two different autoantibodies were identified in this patient’s serum. One was directed against the b2-adrenergic receptor, and increased the beating rate of the cardiomyocytes .........The other autoantibody detected was directed against the muscarinic M2 receptor.....


The plasma exchange success prompted them to start rituximab.

Our patient has required weekly TPE to control her symptoms, thus prompting a trial of rituximab. To the authors’ knowledge, utilization of rituximab for CRPS has never previously been published in the medical literature, though it has been used successfully in dysautonomia.....

...Longer term follow-up is needed before the efficacy of rituximab in this case can be commented on.....

if someone would like a copy of this paper, they can request it from me over in the "Request a paper" thread.

comments?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
This is an interesting case.

This is what I call algodystrophy, because CRPS seems to me to add unnecessary assumptions to a well defined clinical and pathological entity. A useful feature of algodystrophy is that it is objectively measurable - by isotope bone scan or thermography. Moreover, it is completely impossible to conceive of any way in which conscious beliefs about anything, or even unconscious beliefs about anything should induce the regional colour changes, osteopenia and hair and nail growth changes that occur. To treat something like this with CBT is pretty much equivalent to faith healing for cancer I think.

The next point is that the algodystrophic response looks superficially a bit like inflammation but it is unrelated. The limb is cold, perfusion is reduced. Osteopenia is gross and localised to clear embryological domains (not nerve trunk domains) such as carpus or foot or patella. What is intriguing is that there is no known situation in which this response is thought to be useful - unlike inflammation. In that sense it might be a bit like epilepsy - a purely useless byproduct of the way regulatory systems are set up. And the fact that it clearly involves lot of signalling, but without inflammatory markers going up, makes it seem as if it might be a clue to some of the pathways in ME.

I think the crucial factor in interpreting this case and the related cases is the interpretation of the antibody assays. These seem to be reported from several centres and we may be close to a situation where a standard reproducible assay recipe is available for use by regional centres in all developed health care systems. But there are words of caution. Some other autoantibodies that have got popular in a similar way have now begun to look doubtful - to the extent that the physician who invented the assay no longer uses it. Autoantibody tests are easily over-egged. Nevertheless, I am hoping these ones will pan out. They seem to turn up in rather a lot of diseases and different antibodies seem to co-occur in a lot of patients (antibodies to several receptors in one case). This is not quite the picture we see with traditional autoantibodies, but then I am all in favour of considering non-traditional autoantibodies.

What I find most encouraging about this case report is that the patient actually seems to have got better. In my own experience I have never been around when this sort of algodystrophy went away. My understanding is that it can, but that it is unpredictable and many have chronic changes.

Interesting.
 

Hutan

Senior Member
Messages
1,099
Location
New Zealand
So potentially plasma exchange could be used to wash out the putative problematic antibodies in MECFS patients so that there isn't a 7 month wait for the rituximab to kick in?

What's involved in finding the autoantibodies? The excerpts above make it sound routine for those two labs. Did the labs know what auto antibodies they were looking for (ie were the antibodies already known to be present in this particular illness?) or did they just fish about until they found something?

Is there any point in looking for these particular auto antibodies in MECFS patients? Is there any point in individual MECFS patients finding a good immunologist with a research capability and trying to get tested for these auto antibodies?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
So potentially plasma exchange could be used to wash out the putative problematic antibodies in MECFS patients so that there isn't a 7 month wait for the rituximab to kick in?

What's involved in finding the autoantibodies? The excerpts above make it sound routine for those two labs. Did the labs know what auto antibodies they were looking for (ie were the antibodies already known to be present in this particular illness?) or did they just fish about until they found something?

Is there any point in looking for these particular auto antibodies in MECFS patients? Is there any point in individual MECFS patients finding a good immunologist with a research capability and trying to get tested for these auto antibodies?

Plasma exchange might help. It is a laborious procedure and not without risk but it is used in autoimmune neurological diseases. The downside is that the effect only lasts a few weeks from each course.

These autoantibodies are measured using novel assays developed in labs in the US and Germany. Some of the assays are very fiddly because they involve testing samples on live beating rat cardiomyocytes in culture. However, there now appear to be ELISA versions for at least some of them. These particular antibodies were looked for because people are finding them in autonomic syndromes of various sorts. So this was not fishing around to find something.

These antibodies are being studied in ME but I am not able to give details. We will hear about them fairly soon I think. But I do not think there is any point in individuals going to have blood tested. We need well defined cohorts compared to controls in the labs that developed the assays and then getting other labs to reproduce that.
 

voner

Senior Member
Messages
592
These antibodies are being studied in ME but I am not able to give details. We will hear about them fairly soon I think.

it is good to hear that these antibodies are being studied in ME/CFS. I have certainly always been struck by the prevalence of autonomic dysfunction across these syndromes of ME/CFS, fibromyalgia and CRPS (algodystrophy - I had to look up that definition). it sure would help in defining a subset of ME/CFS.

if the autonomic dysfunction is not caused by inflammation, @Jonathan Edwards does it possibly have to do with Brain dysfunction that you described last week...

Then I suspect, next in line in the chain, there is some rather homogeneous problem going on in the brain that explains brain fog and maybe a lot of the autonomic and sickness type symptoms. That might be expected to be in brain stem and limbic areas. It is interesting that data already available suggest some things that are expected and some things maybe not quite as expected - which is good.

but then, how does that fit in with autoantibodies? I am confused, as usual.
 
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Jonathan Edwards

"Gibberish"
Messages
5,256
it is good to hear that these antibodies are being studied in ME/CFS. I have certainly always been struck by the prevalence of autonomic dysfunction across these syndromes of ME/CFS, fibromyalgia and CRPS (algodystrophy - I had to look up that definition). it sure would help in defining a subset of ME/CFS.

if the autonomic dysfunction is not caused by inflammation, @Jonathan Edwards does it pssibly have to do with Brain dysfunction that you described last week...

but then, how does that fit in with autoantibodies? I am confused, as usual.

I think we are all a bit confused. Certainly all the researchers at IiME were a bit confused. Maybe the point about fitting with autoantibodies is that an autoantibody can cause any physiological change you like. It does not have to cause inflammation. It can cause hyperthyroidism or B12 deficiency or paralysis of muscle or whatever. And whatever might be something that never normally occurs - like a leg going blue and cold and nails not growing.
 

voner

Senior Member
Messages
592
I think we are all a bit confused. Certainly all the researchers at IiME were a bit confused. Maybe the point about fitting with autoantibodies is that an autoantibody can cause any physiological change you like. It does not have to cause inflammation. It can cause hyperthyroidism or B12 deficiency or paralysis of muscle or whatever. And whatever might be something that never normally occurs - like a leg going blue and cold and nails not growing.

so, theoretically, could it be a causative factor of pain, also?