Thinking Outside the Box
This is the second of three posts on IVIG treatment and autoimmunity in chronic fatigue syndrome (ME/CFS), POTS and fibromyalgia.
It’s time to start thinking outside the traditional ME/CFS/POTS/FM boxes. It’s possible that if you’ve been diagnosed with these diseases that you may actually have an autoimmune dysautonomia – an autoimmune disease which has attacked your autonomic nervous system. It seems more and more likely that, given the proper testing, a significant subset of ME/CFS/FM/POTS patients will fit into that category.
Dr. Schofield at the University of Colorado and Immunoehealth, Denver, and Dr. Chemali of the Eastern Virginia Medical School, in Virginia, are two of the doctors leading the charge. In a Dysautonomia International video, Dr. Schofield called herself an “autoimmunologist” – one of the few around. A lot of what she does, she noted, doesn’t fit into the current silos in medicine, but then neither do her patients.
A recent study of IVIG’s effectiveness demonstrated what kinds of patients these doctors are treating and how effective the treatments can be.
IVIG Treatment in Autoimmune Dysautonomia
The retrospective study included mostly disabled people with severe autonomic nervous system issues (such as POTS). Most patients were bedridden or nearly bedridden and had been sick for an average of 5 ½ years.
In order to get IVIG, a person needed to:
- Be diagnosed with an autonomic nervous system disorder such as autonomic disorders: postural tachycardia syndrome (POTS), orthostatic intolerance, vasovagal syncope, inappropriate sinus tachycardia, gastrointestinal dysmotility, complex regional pain syndrome and/or neurogenic bladder.
- Demonstrate persistent positivity for one or more autoantibodies that have been associated with autonomic dysfunction.
- Be unable to work or attend school regularly despite standard lifestyle and symptomatic pharmacological therapies.
- Be able to be treated with IVIG at a dose of at least 1 gm/kg monthly for at least 3 months.
- A significant subset of ME/CFS, POTS and perhaps fibromyalgia patients may have an autoimmune dysautonomia.
- People with autonomic nervous system problems, positive antibody tests, a family history of autoimmunity and/or who are unable to work, may have an autoimmune dysautonomia.
- Several traditional antibody tests fail to find evidence of autoimmunity. Newer antibody tests for antiphospholipid syndrome and Sjogren’s Syndrome are, however, often positive in this patient group.
- IVIG was “effective” in over 80% of the participants – many of whom had POTS – in this study.
- A four month trial of IVIG is needed to determine if the treatment is effective. It may take a year or even two for the drug to reach optimum effectiveness.
- Virtually everyone in the study has problems with gut motility.
- Positive small nerve fiber biopsies – common in this group – are very helping in getting insurance coverage.
- Chronic autonomic nervous system problems – perhaps similar to those seen in ME/CFS/FM and POTS – may be triggering autoimmune processes.
Of the thirty-eight patients, 31 were diagnosed with either POTS or orthostatic intolerance. The average age was 36 and most were women. Their average functional score was a paltry 24 out of 100.
The following antibodies were tested for:
- anticardiolipin immunoglobulin M IgM, IgG, IgA
- beta-2 glycoprotein IgM, IgG, and IgA;
- lupus anticoagulant testing;
- anti-phosphatidylserine IgG, IgM, and IgA;
- antiphospholipid syndrome/antibodies;
- anti-prothrombin IgG;
- anti-phosphatidylserineprothrombin, IgM and IgG;
- anti-annexin V IgM and IgG;
- anti-phosphatidylethanolamine IgM and IgG;
- novel Sjögren syndrome panel (carbonic anhydrase-6) IgM, IgG, and IgA;
- parotid secretory protein IgM, IgG, IgA;
- salivary protein-1 IgM, IgG, and IgA;
- thyroid stimulating hormone receptor antibodies, thyroglobulin antibodies, and thyroid
- antinuclear antibody testing including Sjogren syndrome-A (SS-A) IgG,
Sjogren syndrome-B IgG, smith IgG, ds-DNA IgG, NRNP
IgG, centromere IgG; rheumatoid factor, anticyclic
citrullinated peptide antibodies;
- autoimmune dysautonomia panel by Mayo laboratories.
Note that none of the new antibodies being studied in POTS – which are available for testing in Germany – are included! That means that POTS patients didn’t necessarily need to get their blood tested in Germany to find evidence of autoimmunity.
Despite the fact that many of the participants in the study had POTS antibody tests which are not specific to POTS, they were still able to pick up evidence of autoimmunity. (This was primarily due to the high percentage of patients testing positive for novel Sjogren’s, thyroid and anti-phospholipid antibodies.)
Only if the results from the above tests were negative was the CellTrend test for POTS done. That test examines antibodies found by Dr. Kem in POTS patients. They include:
- Angiotensin-II-Receptor-1 (AT1R) IgG-auto-antibodies
- Endothelin-Receptor-A (ETAR) IgG-auto-antibodies
- Beta-1 adrenergic receptor auto-antibodies
- Beta-2 adrenergic receptor auto-antibodies
- Muscarinic cholinergic (M1) receptor auto-antibodies
- Muscarinic cholinergic (M2) receptor auto-antibodies
- Muscarinic cholinergic (M3) receptor auto-antibodies
- Muscarinic cholinergic (M4) receptor auto-antibodies
- Muscarinic cholinergic (M5) receptor auto-antibodies
- Alpha-1 adrenergic receptor auto-antibodies
- Alpha-2 adrenergic receptor auto-antibodies.
To be complete, another series of Celltrend antibody tests have been created by Dr. Scheibenbogen and Celltrend to identify chronic fatigue syndrome (ME/CFS) patients. (All of the ME/CFS antibody tests are included in the POTS panel.)
- Beta-1 adrenergic receptor auto-antibodies
- Beta-2 adrenergic receptor auto-antibodies
- Muscarinic cholinergic (M3) receptor auto-antibodies ELISA
- Muscarinic cholinergic (M4) receptor auto-antibodies ELISA).
Autoimmune Testing Results
Traditional Autoimmune Testing Fails
“We’re capturing only the tip of the iceberg (with traditional testing).” Dr. Schofield
Several important themes emerged. Note that only two patients needed to have the POTS antibody testing done (because their results on the other autoantibody tests were negative). Importantly, traditional autoimmune testing – the antibody testing your doctor is likely to provide – was pretty much a spectacular failure. While forty percent of the participants did have a positive ANA result, other common antibody tests were negative.
To find evidence of Sjogren’s syndrome, most doctors will do the SS-A and SS-B tests, but the SS-A test was positive in only 8% of the patients, and no one tested positive for the Sjogren syndrome-B antibody test. The commonly used rheumatoid factor test – which is often positive in other autoimmune diseases – was positive in only one participant. Shockingly, the Mayo’s clinic’s autoimmune dysautonomia panel – presumably the gold standard in autoimmune dysautonomia testing – was positive in only 13% of patients.
Any doctor relying on these tests would be hard pressed to find any evidence of autoimmunity – and would undoubtedly send his patient home with another diagnosis.
Positive results on the less traditional tests such as antiphospholipid antibodies (76%) and novel Sjögren antibodies (42%), on other hand, were common. (Several studies have found higher rates of these novel antibodies in Sjogren’s patients than the traditional antibodies tested for in the disease.) Thirty-two percent of the participants also tested positive for one or more thyroid antibodies.
Sjogren’s Syndrome (SS) and mast cell activation syndrome (MCAS) got a lot of play at the 2018 Dysautonomia International Conference and it’s easy to see why. Sixty percent of the participants were diagnosed with early Sjogren’s Syndrome, 37% with joint hypermobility syndrome, 32% with thyroiditis and 29% with mast cell activation syndrome (MCAS).
Gastrointestinal motility problems are no surprise given the important role the autonomic nervous system plays in the gut, but the incidence of gut motility issues was still surprising. Every patient in the study had at least some issue with gastrointestinal dysmotility.
A family history of autoimmune disease was present in a remarkable 75% of the patients. (The population norm is 8%.)
The patients were given 1 gm/kg per month in weekly divided doses (.25 gm/kg per week.) The initial rate of infusion was 3 gm/h, or the slowest rate possible to avoid the possibility of aseptic meningitis, then increased by 1 gm/h. Patients were also given 1 liter of saline prior to the infusion. If, after 6–9 months, the patient was not at 80-90% of normal, the dose was gradually increased. Most patients responded to less than 1.3 g/Kg per month.
The response rate (83.5%) was remarkable given this group was, by definition, very difficult to treat. (Exactly what constituted a successful response was not clear in the study.) Many were POTS patients who’d gone through the entire gamut of POTS treatments but remained disabled. The IVIG response rate was similar that found by Dr. Oaklander in children with small fiber polyneuropathy (SFPN) who probably had a similar disease presentation. (Dr. Schofield noted that her patients with signs of autoimmunity, autonomic nervous system problems, and who were disabled, usually tested positive for SFPN, as well.)
For most, the response was gradual, with the average time to first signs of improvement taking over 5 weeks. Since it took some patients 12 weeks to notice improvement, the authors asserted that a 4-month trial was necessary to determine if the drug was effective.
It sometimes took a year or more for the treatment to reach optimal effectiveness – possibly because of the time needed to gradually heal the small nerve fibers. (Dr. Schofield showed a graph of declining Clonidine dosage over two years in one patient as his/her small nerve fibers healed.)
For some the improvement was dramatic; despite the high degree of disability, a few patients were able to regain near- normal functioning. Thankfully for the old-timers among us, duration didn’t matter a whit; even people who had been ill for 20 years responded to the drug.
Causes of Response Not Clear
Further examination of a few participants yielded some intriguing findings that brought to mind Ron Davis’s statements about the complexity of the body. It turns out that some patients received substantial benefits without seeing any improvement in their small nerve fiber loss. That indicated that small nerve fiber problems aren’t necessarily causing the severe impairments these patients were experiencing.
The authors suggested the effects the autoantibodies were having on the neural receptors that effect autonomic functioning are more important, but even then, autonomic functioning test results did not always correlate with improvement; i.e a patient’s autonomic functioning could still apparently remain impaired even if they had experienced significant functional improvement. Something else (they didn’t hazard a guess what) was going on.
The authors also noted that because of how IVIG works, antibody titers are not likely to be helpful in determining improvement either.
Chronic Autonomic Nervous System Problems Tick Off Autoimmunity?
Autonomic nervous system problems are rife in ME/CFS, FM and POTS. Heart rate variability (HRV) studies invariably suggest reduced parasympathetic nervous system functioning (low HRV) in these diseases. It’s not known how much the HRV results affect functioning, but they have been correlated with increased pain, poor sleep and decreased cognitive functioning in ME/CFS and/or fibromyalgia.
Dr. Schofield, in her video and this paper, suggested that chronic autonomic dysfunction could be triggering autoimmune diseases through its inhibition of the anti-inflammatory cholinergic system. The vagus nerve – which controls the parasympathetic branch of the autonomic nervous system – also regulates the anti-inflammatory immune response via the cholinergic pathways. If vagus nerve inhibition is present – as it appears to be in these diseases – then it stands to reason that the anti-inflammatory response is inhibited as well.
The authors suggested that resulting increase in pro-inflammatory cytokines such as tumor necrosis factor (TNF-a) could help set the stage for the appearance of the autoimmune diseases discussed in this paper. Other pathways, the authors said, are possible as well and they suggested that chronic autonomic nervous system problems could also trigger mast cell issues.
If your dysautonomia problems (problems standing, exercising, gut issues, even cognitive issues) are already well treated; i.e. you have normal functioning (definitely not the crowd reading this blog), autoimmune testing may not be needed.
If, however, you cannot work or go to school, if you have a positive antibody test, a family history of autoimmune illness, and your illness began with a common autoimmune trigger (infection, vaccination, pregnancy, concussion or trauma) then the authors believe that autoimmunity should be further explored.
That, in particular, includes testing for antiphospholipid, novel Sjögren’s, celiac, and thyroid antibodies and, if necessary, the adrenergic and muscarinic antibody testing in Germany. (Dr. Kaufman regularly uses the German tests.)
Skin biopsy results were not reported in the paper, but Dr. Schofield reported that patients who have evidence of autoimmunity, have autonomic nervous system problems and can’t work or go to school, also commonly have a positive skin biopsy. That’s important because positive skin biopsy results have been very helpful in getting insurers to cover IVIG.
Given the cost and potential risks of IVIG treatment, the two doctors recommend it only for the more severely ill – a category that would probably fit many people with ME/CFS.
The doctors also recommend a four-month trial of IVIG in patients with disabling autonomic nervous system problems and a positive antinuclear antibody test, positive thyroid antibodies and/or abnormal serum immunoglobulin results, because these findings suggest an autoimmune disease affecting the autonomic nervous system is present.
- An IVIG Chronic Fatigue Syndrome (ME/CFS) / POTS Treatment Success Story: IVIG#1
- Are Chronic Fatigue Syndrome, POTS and Fibromyalgia Autoimmune Dysautonomias? IVIG #2
- The Case for IVIG Treatment in Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, Small Fiber Neuropathy, and POTS: IVIG#3
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