CIDP with antiMAG IgM – are we better off untreated?

    • Anonymous
      April 3, 2007 at 11:56 am

      Dr. Richard Hughes at the Guy’s Hospital, King’s College London, UK, gave an interesting informative workshop at the Symposium in Phoenix. It was entitled “GBS, CIDP or What? Does it Matter? The presentation has been reprinted in the Spring 2007 issue of the GBSFI communicator. He differentiates between the different diseases, describes symptoms, possible causes and treatments. Toward the end of the article (page 7) he talks about a variant of CIDP, paraproteins which are themselves antibodies against a constituent of the nerve called MAG. This variant causes a slowly progressive peripheral neuropathy which is difficult to treat and [COLOR=”Red”]”may best be left untreated.”[/COLOR]

      This last statement really bothered me. It is true that PDN is difficult to treat but there have been positive results with Rituxan and IVIG has helped me eventually albeit not dramatically. Skipping a treatment while in Thailand for two months has resulted in a rapid decline during the last three weeks there. This “experiment” has shown me that at a minimum IVIG slows down the progression and may prevent me from ending up in a wheelchair.

      [I]There are several of us, Allaug, Michaeljay, myself and possible more who have this variant, called PDN by some. I was wondering how they react to Dr. Hughes suggestion to leave PDN/AntiMAG IgM neuropathy alone.[/I]

    • Anonymous
      April 3, 2007 at 3:13 pm


      is this variant detected by a blood test and if so, what is it ?


    • Anonymous
      April 3, 2007 at 3:18 pm

      What can I say, Norb, except “What an arrogant s…-bag”! If I had been left untreated, I would probably not have been here to-day, even if my disease is not fatal in itself. (Well, perhaps I’m exaggerating here, but when I think of how my situation was at the time my haematologist found that there might be a way to help me, and I would have been deteriorating from there, I honestly don’t know!)

      Stacey – it was a combination of blood-tests and bonemarrow biopsy. In the blood-test they can determine if you have an abnormal amount of any of the anti-gens IgG, IgM, IgA, and from the bonemarrow biopsy they can tell if you have a lot of “cloned” B-cells: “Monoclonal Gammopathy of Uncertain Significance”: MGUS. You may have MGUS, which is a kind of benign cancer, without having the anti-Mag Polyneuropathy. Most MGUS patients go untreated, they are just checked to see if the MGUS develope into a malignant type of cancer.

    • Anonymous
      April 3, 2007 at 6:13 pm

      [B]Stacey[/B], in addition to the EMG and spinal tab (no biopsy in my case), they did two blood tests, first SPEP (Serum Protein Electropheresis) and then an immunofixation. I think it was the latter that showed the high titre of antiMAG antibodies. It was done at the neuromuscular lab at Wahington University in St. Louis. It is very expensive and at first the office at the U. of Colorado, where I am being treated, balked at it.

      [QUOTE]”What an arrogant s…-bag”! [/QUOTE].
      I agree, Allaug, except this was not the first time I’ve seen this attitude. Even my own neurologist wrote in one of her notes last year that we wanted to continue IVIG a few more times to see if “it was worth it”. Sometimes I wonder if I am downplaying my symptoms too much and play the hero instead:”Oh, it’s OK, I can handle it.” I don’t talk about not being able write my signature or to pick up a pill I dropped or Carol putting on my socks for me because i can’t do it myself or crawling to a wall to find support for getting up off the floor.

    • Anonymous
      April 3, 2007 at 7:53 pm

      norb, interesting perspective, I’ve seen other institutions and researchers with the same view. Certainly the B-cell depletion is a therapy risky and unsustainable. As you know I’ve been struggling with this issue for some time.

      I’m very interested to hear your perspective on the IV immunoglobin. Most of the research that I’ve seen relative to anti-mag has shown limited efficacy, and I’m following up now with the French and Italian research on interferon.

      My docs are anxious to resume treatments with rituxan, but I’d like to attempt the course with less risky therapies. My docs here don’t have a clear understanding of the protocols and Im following up with the neurology folks in San Francisco. I know they’ve been treating MS patients with interferon with some success.( In an earlier post I made reference to a research paper done in France relative to the use of interferon,for anti-mag follow-up studies by the same folks didn’t show the same efficacy, but there are other research papers showing good response)

      My ataxia, and hand tremors have gotten worse and as you can imagine Im quite concerned. Incidentally I’m using Dragon software for all my typing these days both at home and at school. It’s proven to be a real savior and is about 99 accurate which is certainly better than my typing even on a good day.

    • Anonymous
      April 4, 2007 at 7:29 pm

      Dragon Speak is a wonderful software program. I have a few copies of it for win 95 and 98. I recommend it highly for CIDP’ers with hand involvment.
      (missing “my 2 cents” icon)

    • Anonymous
      April 5, 2007 at 12:03 pm

      Michael, I’ve seen the reports on IVIG effectiveness for antiMAG IgM also. I wonder if there is any real data or if it is mostly anectodal and the different reports are just repeating what others have said/found. It doesn’t surprise me, though, that success rates are low. The immunoglobulin I am receiving, Gamunex, contains according to the leaflet that comes with it, at least 98% IgG and the rest is IgM and IgA. What we probably need is immunoglobulin enriched with IgM. There is one product out there most likely not available here, Pentaglobin. It is made in China, I believe. [url][/url]. The listed literature, however, does not show any use with CIDP.

      IVIG seems to be effective to some extent in [B]my case [/B]with regular 4 week applications. Last year my condition improved to the point that inside the house I was able to move around without support and outside a cane was sufficient. My recent two-month trip to Thailand was, in a sense, an experiment because I skipped a treatment. During the last 3 weeks in Thailand my condition deteriorated significantly and continued to do so here although I received a course of IVIG immediately after my return. But my neurologist warned me right away and told me it might take a second round to show improvement. This is scheduled for next week. It appears there is a certain level of Ig that I (we) require in the blood to have an effect on symptoms. If you look at the half-life of Ig in the serum this makes sense.


    • Anonymous
      April 5, 2007 at 12:22 pm

      I have also been diagnosed MGUS-antiMAG (IgG????). am I missing something here or is this a completely different animal? Have tried steroids and IVIG with minimal results but everytime I mention rituxan to my neurologist he frowns and changes the subject. Has rituxan been shown to only be effective with IgM? The literature and studies I have found seem to indicate this. Answer anyone please?
      Let me add my three cheers for Dragon Naturally Speaking. It and my 3wpm hunt and pick pencil allow me to stay in touch even though my hands and feet are almost completely numb.
      Thanks. Morris

    • Anonymous
      April 5, 2007 at 11:17 pm

      Norm I’m beginning to understand some of the theories behind the reported efficacy of interferon, and I have to admit I’m still clueless relative to the imminugoblin approach??

      Did your neurologist follow a standard protocol for this??

      thx for the link will check it out

      I agree they are certainly have been mixed reports in the literature./
      one of my docs said “we are kinda of feeling around in the dark here”
      and I very nervous about going back to rituxan

      Morris/ I thought that most anti-Mag were indeed the Igm flavor/ but all of these are immune mediated and have their sources at the B-cell level.
      One interesting study that I saw showed minimal impact on titre for IgA and IgG while a significant impact on IgM again with no detectable B-cell in serum. The authors hypothesized a number of potential reasons why
      do a search on Pestronk “the father of anti-mag rituxan therapy”

    • Anonymous
      April 5, 2007 at 11:20 pm

      Norb…sorry “norb” on dragon is norm…:)

    • Anonymous
      April 6, 2007 at 11:28 am

      Michael, maybe this is of interest. Before the hacker atttack on this forum, I had some discussion on IVIG and antiMAG with “Threads”, an immunologist. Unfortunately she no longer participates on the forum.

      Thanks to Allaug we rediscovered two of her posts in an archive. Here is what threads wrote in 2005:

      Junior Member
      Registered: Dec 2005
      Location: Northern California
      Posts: 20
      Norbert – this isn’t a really solid answer because the mechanisms by which IVIG work aren’t fully understood. But I think this is reasonable based on what we do know.

      First – back to some basic immunology. As you know, there are different classes of antibodies: IgM, IgG, IgA, IgE, and IgD. The class is determined by the “heavy chain” (antibodies all have heavy and light chains). The heavy chain is a protein which is roughly 25% “variable region”, and 75% “constant region”. The variable region is the part of the antibody that binds to antigen, and it is called variable because there are so many different protein sequences. The variable region, or binding site, can actually be the same for antibodies of different classes.

      The constant region of the antibody determines which class it is. There is a distinct sequence for the mu chain (which makes IgM), for the gamma chains (IgG), for the alpha chains (IgA), and so on. While the role of the variable region is to bind antigen, the role of the constant region is to stabilize the protein, to connect to the light chains, etc., and to bind to receptors on cells like macrophages and granulocytes. These receptors are called Fc receptors (Fc is for constant fragment).

      Most of the time antibodies work by (a) binding to antigen on one end of the protein and (b) binding to an Fc receptor on the other end of the protein. Binding to the Fc receptor activates all sorts of cells and can lead to release of molecules that cause inflammation, to activation of phagocytic cells that engulf whatever the antibody is binding to, and other immune mechanisms.

      The antibodies in IVIG are primarily IgG class – that is the class of most normal serum antibodies. One action of IVIG is to downregulate Fc receptors – for the IgG class. There have been other proposed mechanisms for IVIG action and some or all might be a part of the package. But it seems that most of the mechanisms are related to the massive infusion of a lot of IgG constant regions, and are not due to specific antigen binding properties of the IVIG. You can see that it will not have the same effect on IgM specific receptors because there is not a lot of IgM class antibodies being infused.

      I think this is why it is important to figure out whether someone has a pathogenic IgM causing the disease (and so less likely to respond to IVIG), vs. someone with typical CIDP that happens to have a benign IgM spike in their serum.

      My speculation is that there are also patients where the disease doesn’t involve a lot of antibody production; that it is primarily T cell or NKT cell mediated, and that those patients are also IVIG unresponsive. The clinical literature has noted that patients with a longer course of disease tend to be less responsive to IVIG, and it may be that for typical CIDP (unlike anti-MAG IgM) the antibody component decreases over time and the T cell component becomes predominant.


      Norbert – from I can tell, it does seem like the predominantly IgM mediated conditions have a different underlying pathology from the more typical CIDP.

      This is what I know about the basic immunology. When B cells develop, they first make IgM antibodies on their cell surface. Very little, if any, is secreted. The IgM antibodies are very low affinity, but somewhat stickier than other antibody classes because they have 10 binding sites, not 2. When the B cells are stimulated by antigen, they secrete IgM for short periods of time, then either die or interact with antigen specific T cells.

      With T cell interaction, the B cells switch to IgG class antibodies (gamma globulin), which gets selected for high antigen affinity, and high levels of secreted antibody into the blood.

      As we get older, it is not that unusual for the odd B cell clone to misfire and fail to die when they reach the terminal IgM stage. They produce moderate amounts of IgM antibody that is low specificity, and as long as the antibody doesn’t stick to anything it is harmless. Apparently in some cases the antibody does react with a myelin component, hence causing the damage that you have unfortunately observed.

      The point behind the immunology is that a whole different class of cells is involved with this condition than with typical CIDP. It is likely that T cells are out of the picture (and might even be helping), so steroids don’t work, along with cyclosporine and various other drugs that alter T cell function.

      In addition, the autoantibody is different than typical CIDP. In many cases of CIDP there is an IgG class antibody (produced by B cells but requiring T cell interaction). The current wisdom in IVIG is that at least of its activities is to block/down-regulate the receptor for IgG constant regions (Fc receptors) on effector cells. In effect, the IgG class antibodies stick to myelin, then cause non-specific cells to come over and cause damage. By downregulating the receptors on the non-specific cells, the antibodies are still around but they don’t cause damage.

      The Fc receptors for IgM are different, and the IgM may be causing damage by other mechanisms, like formation of immune complexes, or by just glomming things up in general, so IVIG is also often ineffective for your condition.

      The bottom line is that you want to target that B cell clone, and maybe clear out the autoantibodies in your blood. Hopefully your rituxan will be effective – I would put that as a first line drug for MGUS/anti-MAG. Azathioprine is another drug that targets B cells. There is a monoclonal in clinical trials that targets CD22 on B cells, Epratuzumab, which might be worth looking into, and anti-CD19 antibodies on the horizon for the same purpose.

      I have seen conflicting reports on the efficacy of plasmapheresis – it seems like it should work, but maybe the filter needs to have the adsorbants to get out IgM? In theory anyway, it seems like PP should also be able to give you relief.

      Thanks for the link you sent, and let me know how your treatment goes.
      Report this post to a moderator | IP: Logged
      12-19-2005 08:05 PM

    • Anonymous
      April 8, 2007 at 8:37 am

      [QUOTE]Another example of CIDP associated with a paraprotein is the POEMS syndrome. This acronym stands for polyneuropathy, organomegaly (enlarged organs like the liver), endocrinopathy, monoclonal protein (a paraprotein) and skin changes (such as increased pigmentation and hairiness). …. treated with irradiation which is followed by gratifying improveent in the peripheral neuropathy. [/QUOTE]

      [QUOTE]Endocrinopathy: Literally, a disease of an endocrine gland. A medical term for a hormone problem. For example, hyperthyroidism, hypothyroidism, etc. [/QUOTE]

      Which paraprotein is this? Which blood test can show it?

      Does the above quote from the article mean that you can have CIDP and endocrinopathy or that endocrinopathy (and each of the other mentioned) can be the CIDP problem?

      Is the paraprotein related to the measurement of antibodies?

      Endocrinopathy – hypothyroidism – Hashimoto’s (high TPO-antibodies) is my case. I would like to know how this is all related and treated. The article leaves too many questions for me.

      Any answers???

    • Anonymous
      April 8, 2007 at 1:11 pm

      Nina, I don’t have an answer to your questions except a laypersons view. Paraproteins can create antibodies with many different shapes of binding sites. I our case the binding site happens to fit MAG. Others can fit other body organs and cause damage. In most cases as Threads in my earlier quote points out, they are harmless. Paraproteins occur in large quantities and show up as spikes on – I believe on a SPEP – test. A follow-up immunofixation test would identify in detail what in our body the antibodies react to. [QUOTE]Immunofixation is a laboratory technique. It is similar to immunoelectrophoresis, and enhances the results of standard protein electrophoresis. Electrical charges are used to separate proteins from a sample.

      Immunoglobulins appear as a gamma band of proteins. Laboratory techniques are used to further identify the individual immunoglobulins. Immunofixation gives more rapid results than standard immunoelectrophoresis, and it is somewhat more sensitive
      [/QUOTE] The test results in my case showed no reactions to several components which didn’t mean much to me except MAG which was high

    • Anonymous
      April 8, 2007 at 2:19 pm

      Norb, nice material thx so much

      some interesting follow-up from Funk “Turmeric Prevents Experimental Rheumatoid Arthritis, Bone Loss, University Of Arizona”

      the folks here are looking hard at rituxan for RH given that its B-cell mediated. i find it extremely interesting that they cite transcription factor called NF-KB which is also cited in the anti-mag literature.

      your thoughts??

    • Anonymous
      April 10, 2007 at 9:17 am

      [QUOTE]”What an arrogant s…-bag”! [/QUOTE] Allaug. Prof Richard Hughes is definitely not arrogant. He is quite eminent in the contribution that he has made to the investigation and treatment of peripheral neuropathies.
      He was a tremendous support to Glennys Sanders in the founding of the GBS Support Group UK, is on the Medical Advisory Board and on that of GBSFI.

      At GBSG UK conferences he has always had the ability to inform his listeners in readily understandable ways and certainly not as if he was addressing a group of fellow neurologists. The last thing we would call him is that particular description!”

      I have not yet seen the article. In an article “Management of Inflammatory Neuropathies” (2003) co-written with Dr Robert Hadden of the West London Neurosciences Centre on JNNP Online there was a section on Paraproteinaemic Demyelinating Neuropathy. They described anti-MAG IgM as the best defined PDN condition. They went on: Mild slowly progressive disease is best left untreated. In more severe cases, IVIg has a transient beneficial effect (level 1b evidence). Fludarabine and rituximab have seemed effective in small series of severely affected patients.

      That was 3+ years before the GBSFI symposium. Further on a joint task force of the European Federation of Neurological Studies and the Peripheral Nerve Society published PDN guidelines. The task force included Prof Hughes and Richard Hadden (team leader?).
      It includes:[QUOTE]IgM PDN.
      A recent Cochrane review of anti-MAG paraproteinemic neuropathy concluded that there is so far inadequate reliable evidence to recommend any particular immunotherapy (Lunn and Nobile-Orazio, 2003). The same conclusion may be extended to IgM paraprotein-associated neuropathy without anti-MAG antibodies. Based on evidence regarding the pathogenicity of anti-MAG antibodies, therapy has been directed at reducing circulating IgM or anti-MAG antibodies by removal [plasma exchange (PE)], inhibition [intravenous immunoglobulin (IVIg)], or reduction of synthesis (corticosteroids, immunosuppressive agents, cytotoxic agents, or interferon-α). Only five controlled studies on a total of 97 patients have been performed (Lunn and Nobile-Orazio, 2003). [/QUOTE]
      The humanized monoclonal antibody (Rituximab) against the CD20 antigen was tested in several recent open pilot trials. In an open prospective study, over 80% of 21 patients with neuropathy with IgM antibodies to neural antigens (including seven with PDN and anti-MAG IgM) improved in strength after 1 and 2 years, compared with none of 13 untreated patients (Pestronk et al., 2003) (class III). The average improvement in strength was 13% at 1 year and 23% at 2 years. However, it was not reported how many patients with anti-MAG antibodies improved or whether Rituximab improved the sensory ataxia, the most frequently disabling feature. No response to Rituximab was observed in two patients, including one with an IgM monoclonal gammopathy-associated chronic motor neuropathy with anti-ganglioside IgM antibodies (Rojas-Garcia et al., 2003). Six of nine patients with chronic polyneuropathy with IgM monoclonal gammopathy and anti-MAG IgM treated with Rituximab in an open phase II study had detectable improvement (defined as ≥2 points improvement in the neuropathy impairment score), two remained stable, and one worsened (Renaud et al., 2003). However, only two patients had clinically useful improvement (≥10 points), and four had marginal improvement (5 or less) (class IV).

      Good practice points for treatment of IgM PDN

      1 In patients without significant disability, consideration should be given to withholding immunosuppressive or immunomodulatory treatment, providing symptomatic treatment for tremor and paresthesiae, and giving reassurance that symptoms are unlikely to worsen significantly for several years.

      2 In patients with significant disability or rapid worsening, IVIg or PE should be considered as initial treatment, although their efficacy is unproven.

      3 In patients with moderate or severe disability, immunosuppressive treatment should be considered, although its long-term efficacy remains unproven. Preliminary reports suggest that Rituximab may be a promising therapy.

      4 More research is needed.

      The whole report may be found at: [url][/url]

    • Anonymous
      April 11, 2007 at 7:03 am

      [B]”may best be left untreated”[/B] – it mad me so angry, Ken, because if I had been “left untreated”, when I think back on my condition pre Rituxan\Fludarabine treatment and imagine a worsening from there, I don’t know if I had been able to cope – and who knows where I’d been to-day. Perhaps nowhere……

      Of course it was wrong of me to react to such a short quote, when I read your post just now, I can see that it was taken out of a very mitigating context!

      What is scary, though, is not being sure about the criteria for getting the best treatment. I don’t know why they ( the neurologists) are so sceptical to Rituxan, and why they only talk about improving in strength.

      [COLOR=”DarkOrange”]”it was not reported how many patients with anti-MAG antibodies improved or whether Rituximab improved the sensory ataxia, the most frequently disabling feature.”

      what kind of conclusion is that? I don’t know if I’m part of a study, but I HAVE IMPROVED GREATLY and MY ATAXIA IS GONE if not completely, there are now only a few things I still cannot do (like using “touch” on my keyboard).

      I’ll say I’m sorry for responding to something without knowing the full context, Ken. I’m so happy for everything you tell me prof. Huges has done for people like us.

    • Anonymous
      April 22, 2007 at 10:45 am

      Just back from the UK GBS Support Group conference at Swindon. The opening speaker was Prof Richard Hughes on “GBS and CIDP. The knowns and the unknowns.” {By the way he is retiring later this year but he will continue his international connections and association with the Cochrane reviews. Retiring he may be from his main calling at Guy’s/Kings London but not from neurology.]

      Delivered in his usual clear and infomative way for an interested but not medically educated audience one of the things he stressed was the importance of randomised, controlled trials of treatments. The afternoon period includes an “Ask the Experts” session. By chance 2 of us had put in similar questions about Rituxan/Rituxaban. Prof Hughes, after briefly explaining about PDN and especially about anti-MAG IgM neuropathy, said that there has now been a randomized contorlled trial of 24 patients and that the 12 who were treated did better than the 12 placebo patients. A joint Swiss/French trial of 60 patients is now under way and results are awaited with great interest.

      Everyone respects the way in which Richard Hughes regards his audience. He always says that at such a conference the audience knows much more about the inflammatory, demyelinating disorders than his students. The audience has years of experience after all and many have acquired much knowledge!:o