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“The bottom line is that we should rethink this whole area and encourage proper clinical trials.” Dr. Nancy Klimas

This article is the last of a three-part series on IVIG which came out of my attending the 2018 Dysautonomia Conference in Nashville, Tennessee.

IVIG evidence ME/CFS

What evidence exists for the use of IVIG in ME/CFS, FM and POTS?

IVIG is a very expensive but commonly prescribed immune modulating drug used extensively in autoimmunity and immune deficiency. The article examines the evidence base for IVIG in chronic fatigue syndrome (ME/CFS), fibromyalgia and POTS and looks to the future to see what possibilities may emerge.

I queried ME/CFS experts on their use of IVIG in ME/CFS/FM and did a literature search. Four experts answered – Dr. Lapp, Dr. Sivieri, Dr. Klimas and Dr. Levine. Dr. Lapp and Dr. Sivieri sent short replies and Dr. Klimas and Dr. Levine – both obviously very interested in this drug – sent several page-long answers. Dr. Klimas, an immunologist, provided both a historical and present-day overview of the drug’s use in ME/CFS.

About IVIG (Intravenous Immunoglobulin) Treatment

Available since the 1950s, IVIG contains massive amounts of gamma globulins or antibodies which are gathered from the plasma of at least a thousand healthy donors. (Dr. Schofield noted in her video, though, that it probably comes from many thousands more.) Filtering the plasma to get the antibodies and produce the IVIG takes upwards of nine months.

Dr. Klimas believes that the pooling of IVIG from a large population gives it a “tremendous advantage”. If an infection is the problem, then potential protection provided by the product is so complete that you don’t necessarily need to know what virus is present – you just need to boost your immune functioning with the product.

IVIG is a blood product used to fight off infection, boost immune system functioning or tamp down inflammation in people with inflammatory, autoimmune or neurological diseases like Guillain-Barre syndrome, lupus, multiple sclerosis and others. People with immunoglobulin deficiency states (low levels of immunoglobulins or immunoglobulin subclasses) who experience recurrent infections are eligible for IVIG.

First used to boost the immune systems of people with immune deficiency disorders, IVIG is now mostly used as an anti-inflammatory treatment to combat autoimmune disorders.  It’s been used in virtually every autoimmune disorder.  Dr. Klimas reported that the list of diseases treated with IVIG grows longer every year. IVIG has an advantage over some of the monoclonal treatments used in autoimmune diseases because it’s safer and not as immunosuppressive.

It’s also used as a treatment of last resort in a number of disorders.

Three Types of Gamma Globulin Products

Gamma globulins can be administered in three different ways – via infusion (IVIG), subcutaneously, and intramuscularly.

Intravenous gamma globulin (IVIG) – The most commonly used form of gamma globulin is administered intravenously, usually once a month but sometimes weekly. If it’s administered monthly, IgG levels will rise and then dip, leaving a gap in coverage during the month.

Subcutaneous gamma globulin – One advantage of the subcutaneous product is its ability to be self-administered. Dr. Lapp pointed out that you can even throw it into your suitcase and travel. The fact that it produces steady levels of immunoglobulin makes it probably more effective in people who are fighting off infections. Dr. Levine reported that she’s switching some of her patients to weekly subcutaneous injections of Hyzentra in order to achieve more even levels of gamma globulin in their bloodstream.

The subcutaneous form has mostly been used to restore immunity and fight off infections, but Dr. Klimas reports that for people with autoimmune diseases a single high dose IV infusion followed by weekly, lower dose subcutaneous injections can be effective as well.

Intramuscular gamma globulin  – is not commonly used. In the first 10 years of her career (80s and early 90s), though, Dr. Klimas reported that she used a lot of IM gamma globulin and her clinical impression was that it was very helpful.  During the Gulf War (1991), however, the army bought all of the available IM gamma globulin and it was off the market for several years. When it came back on the market it was prohibitively expensive.

Now, even though intramuscular GG is less expensive than intravenous gamma globulin, she’s rarely able to get it. She finds it easier to get IVIG or the equally expensive subcutaneous product.

Brand

IVIG is produced by a number of companies that make different brands of IVIG. Because the IVIG brands can differ in so many areas (concentrations, formulation, osmolality, product stabilizers, sodium concentration, anti-infective activity, IgA content and pH) it can, at times, be important to match the patient to the right brand of IVIG.

Dr. Levine prefers Gammagard. Dr. Klimas reported that the insurance company usually decides the brand and her experience is that the results are generally similar across brands.

Dosing Regimens and Safety

IVIG is usually given every couple of weeks, often needs to be given continuously (not a cure) and is incredibly expensive (can cost $100K a year). The risk of aseptic meningitis is low but increased in patients with autoimmune dysautonomia. That problem can be ameliorated by slower infusions and hydration.  Blood clots and kidney toxicity are two other rare complications.

Two dosing regimens exist: a low dose one for patients with low antibody levels (immune deficiencies) and a higher dose for patients with autoimmune dysautonomia who need the extra antibodies in the high-dose IVIG to swamp the bad ones producing their disease.

Schofield usually starts out with 1 gram/per kg in her autoimmune patients, and that’s usually enough, but she can go up to two g/kg monthly.

Schofield warned that giving IVIG slowly and using aggressive hydration is important in her POTS patients. She generally starts off with 1/4 g/kg weekly and works up to 1 g/kg given all at once. (Some patients peak at ½ g per kg. She warned never to give IVIG and fluids at the same time.)

Schofield and Dr. Klimas agreed that in ME/CFS (where IgG1 and IgG3 – which fight off viruses are more important), weekly injections are more likely needed to ensure constant antiviral protection in some patients because the half-lives of these antibodies are shorter.

Why IVIG Works When it Does

IVIG antibodies chronic fatigue

IVIG provides antibodies that can boost and rebalance the immune response.

Many different hypotheses have attempted to explain IVIG’s success. One idea is that it stops autoantibodies from binding to their targets. Another is that it binds to and halts autoreactive B-cells that produce dangerous autoantibodies. Yet another is that it hastens the degradation of pathogenic antibodies or that it scavenges complement (C3b, C4b) proteins before they can cause tissue damage. All these hypotheses may, in fact, be accurate in different diseases.

IVIG in Chronic Fatigue Syndrome (ME/CFS)

Studies

Significant interest in gamma globulin resulted in several clinical trials in the 1990s that had mixed results.  Peterson’s 33-person placebo-controlled blinded 1990 study found widespread evidence of immunoglobulin deficiencies. Despite restoring some of the deficiencies, the six-month trial of IVIG given monthly found no evidence of significant improvement.

Hickie et. al. found improved mood and immune functioning in a smaller 1992 IVIG trial and Lloyd’s placebo-controlled 1990 trial found significant improvement in approximately 40% of patients with many resuming work and other activities.  Lloyd’s larger 99-person 1997 follow-up trial, however, was unsuccessful, as was a smaller American trial that targeted IgG deficient individuals. The Lloyd study, the largest ever done in ME/CFS, found high levels of side effects and reported that “Intravenous immunoglobulin cannot be recommended as a therapy for the treatment of CFS. A better understanding of the pathophysiology of this disorder is needed before effective treatment can be developed.”

Dr. Klimas, however, pointed out two glaring problems with the study. First, it included autoimmune (high dosing) patients and it used a subpar product whose impurities eventually forced it from the market. If the dosing had been lower and a different product had been used, the outcome might have been different. Plus, the trial only lasted for three months.

Dr. Klimas believes that Stephen Straus’s 1997 editorial, “Intravenous Immunoglobulin Treatment for the Chronic Fatigue Syndrome”, published in the American Journal of Medicine, effectively put an end to IVIG clinical trials in ME/CFS.

Rowe’s 1997 IVIG trial, on the other hand, found significant functional improvement as did her five year follow-up.  Rowe’s five year follow-up was reported in a publication (Journal for Chronic Fatigue Syndrome) that was unfortunately not included in medical indexes such as PubMed and therefore was not widely disseminated.

In 2003, Jonathan Kerr reported that IVIG treatment in three cases of parvovirus associated ME/CFS led to a resolution of symptoms, improved functional ability and normalized cytokine tests.  A 2005 case report of a young boy with parvovirus associated ME/CFS treated with IVIG had the same result.  A 2015 case report of an ME/CFS patient with documented parvovirus infection, however, found IVIG had a paradoxical effect, increasing viral replication and symptoms.

Autoimmunity, Inflammation and ME/CFS

Dr. Levine reported that the finding of antibodies against the receptors on blood vessels in a subgroup of ME/CFS patients may open the door for these patients to be treated for ”autoimmune autonomic gangliopathy”.  Studies are underway at several centers to assess IVIG’s effectiveness in these patients. If the results are positive, that should open the door for the use of IVIG in ME/CFS patients with high levels of these antibodies.  The German CellTrends lab is the only lab doing these tests at the moment.

Dr. Levine reported that another possiblly helpful diagnosis for obtaining access to IVIG treatment is ”inflammatory neuropathy” (burning, pain, tingling in the extremities and sometimes loss of reflexes and/or abnormal EMG response) which has been validated by a neurologist.  (The dosing schedule for inflammatory neuropathy is a bit higher and more frequent (1-2 gms/kg for a 50 kg woman or 50 to 100 gms daily for two days in a row every 2-3 weeks for a total of five or six doses.)

Dr. Klimas believes gamma globulin could offer a two-for-one option for one set of patients: ME/CFS patients with an immune deficiency and viral reactivation but who also have an autoimmune condition.

See below for autoimmune diagnoses which may in the future assist some people with ME/CFS get IVIG.

Effectiveness

IVIG appears to be like many other drugs/treatments for ME/CFS. Some people – probably a small percentage – do really well, more do moderately well, and some do not respond at all. Dr. Sivieri has reported before that IVIG can be effective but believes it works best when administered within a total treatment paradigm.

In Dr. Levine’s experience, gamma globulin given either intravenously or subcutaneously is a moderately effective treatment in ME/CFS patients who frequently suffer from upper respiratory infections or who experience chronic flu-like symptoms.  If infections are a problem, sometimes she’ll reduce the infusion frequency (to every 6 weeks) during the summer months.

IVIG’s effectiveness should increase as the autoimmune subsets in ME/CFS/FM and POTS become better elucidated and more easily targeted.

Getting Coverage

All the experts agreed that insurance companies want to see evidence of an immune deficiency and active infections. Dr. Lapp reported he only had a low number of patients on the products because insurance companies will “fight harder than a marlin on a hook” to keep from paying.  Similarly, Dr. Sivieri wrote that while he is still “doing a fair amount” of IVIG, it is, in his experience, getting harder and harder to get insurance companies to cover it. If the trend continues, he worries about IVIG becoming a “lost” treatment.

Dr. Levine reports that insurance companies most commonly want test results showing that a person’s immune system does not get boosted by a vaccine shot.  If the immune boost is not seen, the patient is diagnosed as having Common Variable Immunodeficiency (CVID) and can be eligible to receive monthly IVIG infusions.

Even though “dead” vaccines seem less problematic than live vaccines in ME/CFS, administering any kind of vaccine to an ME/CFS patient can be problematic. Since insurance companies have decided that the vaccine test is the gold standard for coverage, getting it via other routes is more difficult.

Lacking the vaccine challenge, Dr. Levine’s experience is that at least four annual episodes of sinusitis, bronchitis or other infections requiring the use of antibiotics are needed to get covered.  (A bout of sinusitis can send some people into a relapse and IVIG can stop that.) She noted that insurance companies will sometimes even request receipts for antibiotics from the pharmacy to show that the patient has filled these prescriptions.

Finding evidence of autoimmunity (autoimmune polyneuropathy, autoimmune autonomic gangliopathy) is another option which may emerge in the next couple of years.

If you have ME/CFS or fibromyalgia, keep reading! The next sections may apply to you.

IVIG in Small Fiber Neuropathy (Polyneuropathy)

These families’ relentless testing for treatable causes of their children’s chronic pain generated the abundant data analyzed here. Oaklander and Klein

Dr. Oaklander reported some promising results using IVIG in children with a putative diagnosis of small-fiber polyneuropathy (SFPN); e.g. small fiber neuropathy (SFN). SFPN or SFN has been documented in fibromyalgia and  is being documented in chronic fatigue syndrome (ME/CFS). (Both Dr. Systrom and Dr. Kaufman have found it extensively in ME/CFS; Systrom will presumably report on this soon in a study.)

small fiber neuropathy POTS

Findings of a small fiber neuropathy can help one’s chances of getting IVIG.

This was an ME/CFS/FM/POTS/EDS type group for sure. The most common “label” attached to these patients was fibromyalgia. Others included most of the long list of diseases or conditions associated with this illness complex: “functional disorder”, central sensitization, chronic fatigue syndrome (ME/CFS), POTS, irritable bowel syndrome, migraine, chronic headache, EDS, myofascial pain syndrome and chronic (treatment resistant) Lyme disease.  Almost 70% of the participants were disabled. Sixty-one percent attributed the onset of their illness to an instigating infection or injury.

IVIG was tried in eight patients who didn’t respond to corticosteroids or who required long-duration treatment. Three did not respond but five received significant improvements including, in those who were tested, improvement on autonomic tests (Tilt, Valsalva, heart rate variability).

Autoimmune SFPN (AaSFPN)

Now calling the condition “autoimmune SFPN (aaSFPN)” Oaklander’s larger IVIG study (n=55) found 74% of the participants rating themselves ‘improved’ and their neurologists calling 77% of them IVIG responders.  Almost 40% reported that they were “very much improved”. Ten percent reported they were worse.  For some reason, males responded spectacularly with 100% improvement rates while females had 61% improvement rates.

Sixteen percent of the participants entered a sustained long remission (average of 20 months). The study, interestingly, tried the highest suggested dose first (1.3–2.0 g/kg/4 weeks) and then titrated downwards, if necessary. It also lasted longer than many trials (at least 3 months).

Only one-quarter of the participants had a “systemic” autoimmune diagnosis (high ANA titers) while three quarters had a small fiber autoimmunity that was restricted to the small nerve fibers in the body (and wouldn’t be picked up by standard blood tests).

Except for transient infusion reactions (headaches, nausea, flu-like symptoms, stiff neck) which were common (60%) and addressed by slowing infusion rates, hydrating patients, etc., side effects were low.

The authors asserted that their results “imply that aaSFPN may be far more common than appreciated” and “provide strong evidence that medical insurers should no longer reflexively decline to pay for IVIG treatment of aaSFPN.”

The data is clearly calling out for a large placebo-controlled trial in SFPN. Given the rigorous classification of the patients, a successful larger trial could open the door for treatment of a significant subset of ME/CFS/FM patients with documented SFPN.

Fibromyalgia

Back in 2008, Carol found that a third of fibromyalgia patients had a chronic demyelinating polyneuropathy. He reported that a brief IVIG treatment significantly improved pain, tenderness and strength.

Postural Orthostatic Tachycardia Syndrome (POTS)

No studies have examined IVIG’s effectiveness in POTS, but Goodman reported good results at the 2018 Dysautonomia conference and recently published a case report in which IVIG, low dose naltrexone and antibiotics (for SIBO) resolved the POTS of a severely ill patient.

In 2018, Dysautonomia International funded the first placebo-controlled pilot IVIG trial ever in POTS. (The trial is already filled but if it succeeds a larger trial will open up.)

Conclusion

The case for the use of IVIG in treating ME/CFS/FM/POTS in the medical literature has mostly consisted of small clinical trials and case reports. The findings are mixed with more recent, better targeted studies being more positive, but the studies are too small and lack the rigorous placebo controls needed to get doctors to prescribe it or insurance companies to cover it. Larger studies are underway, however.

Suzi’s successful IVIG story demonstratives how effective the drug can be in the right ME/CFS/POTS patient. The real excitement with IVIG lies in the future with the validation of autoimmune subsets which affect the small nerve fibers the blood vessels or possibly the mitochondria in ME/CFS, FM and POTS. The emergence of those subsets will likely result in the reconfiguration of the ME/CFS/FM/POTS disease group.  Successful IVIG trials in autoimmune POTS and small fiber neuropathy, if they occur, should open the door for more insurance coverage of this expensive drug in these groups.

IVIG Series

Other Articles from the Dysautonomia Conference

Your Support Is Needed

The Nashville conference was one stop on an East Coast trip which provided a gold mine of information, inspiring new insights and a wealth of articles.  Upcoming blogs include one on Dr. Klimas’s exercise study, a possible new treatment for fibromyalgia, talks with Jarred Younger, Avindra Nath, Vicky Whittemore, Dr. Pridgen and – on the return home – the folks at the Bateman-Horne Center. Next up on the travel agenda is the Stanford Symposium. Travel provides many opportunities but travel to the East Coast, in particular, is expensive for a small organization like Health Rising which hasn’t even begun to recoup its trip costs. If you find conference reports and other travel related blogs helpful and want to see these in the future, please support Health Rising.

 

 

 

 

 

 

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