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  Myasthenia  updated March 2011

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Intravenous Immune Globulin in the Treatment of Myasthenia Gravis

by Steven Novella, MD
Assistant Professor of Neurology
Yale University School of Medicine
January 2004

It has long been known that Myasthenia Gravis (MG) is an autoimmune disease; the immune system, which evolved elaborate mechanisms to identify self from non-self, is imperfect and may become activated against one's own tissue. In the case of MG, antibodies are formed which attach to the Acetylcholine receptor on the post-synaptic neuromuscular junction, blocking the chemical signal connecting the nerve and muscle and resulting in weakness. (At least in most patients, there are subtypes of MG with similar but distinct mechanisms, such as the recently discovered MuSK Ab positive subtype.)

Treatment of MG is therefore similar to all other autoimmune diseases - namely, immune function must be suppressed. Over the years an armamentarium of immuno-suppressive drugs and treatments has been developed to treat autoimmune diseases such as MG. One such treatment, intravenous immune globulin (IVIG) is the focus of recent interest for an expanding role in the management of MG.


IVIG in MG

Historically IVIG has been used in MG as an acute therapy for MG crisis. In this way it has primarily been an alternate therapy to plasmapheresis. IVIG has been shown to have similar efficacy to plasmapheresis in the treatment of acute MG exacerbations2. It has also been shown to be effective in treating patients prior to thymectomy in order to improve their ability to handle the anesthesia and surgery3. The evidence for effectiveness, however, is not yet definitive, and more studies would be helpful.

Another similar use of IVIG is for severe refractory MG, patients who have not come under control with standard treatment4. In these cases IVIG can be given over a short course in order to bring the patient under control, but traditional long term medications are still used to maintain control.

Recently there has been a great deal of interest in using IVIG to chronically treat MG. There are already small studies which show that IVIG may be effective if used in this way 5,6,7. More study is required before IVIG is likely to be accepted broadly for this use.

The potential advantage is not that IVIG is likely to be more effective than current treatments. The published studies and consensus of clinical experience is that IVIG is likely to be as, but not more, effective as plasmapheresis. Also, the standard combination therapy of prednisone for short term treatment (usually around one year of treatment tapering either to a very low dose or completely off) with long term immunosuppressive therapy with either azathioprine, cyclosporine, or Cellcept has proven to be very effective in controlling MG is most cases. It is unlikely that IVIG will prove to be more effective than these established therapies. It is important to note, however, that these "established" therapies, although supported by some studies, are far from proven by large definitive clinical trials.

What is driving the interest in IVIG for chronic therapy is not improved efficacy but decreased side effects. Plasmapheresis long term has the major disadvantage of requiring the placement of an intravenous catheter. Such catheters are prone to either clot off or become a site of infection. IVIG also requires venous access, but not as large a bore as for plasmapheresis. Therefore, routine peripheral venous access may be adequate in most cases.

Prednisone also has an unattractive side effect profile. Prednisone decreases resistance to infection more than IVIG. It also suppresses many of the symptoms of infection, like fever and swelling, and therefore an infection may go unrecognized longer. Prednisone counteracts the effects of insulin and may cause a temporary diabetes. It also predisposes to gastric ulcers, weight gain, and osteoporosis. Less common, but very serious, side effects include aseptic necrosis of the head of the
femur (essentially, severe arthritis of the hips) and steroid induced myopathy (muscle damage). Long term steroid use can therefore, ironically, cause weakness.

Cost of IVIG treatment, however, is a concern, as prednisone is very cheap (cost estimates are at less than $50 per year) and IVIG is very expensive (total cost would be in the tens of thousands of dollars per year). However, there are many hidden or secondary costs of prednisone therapy. Patients on prednisone must also be treated with medication to protect from gastric ulcers, need to be on calcium supplements and perhaps also other agents to prevent osteoporosis, and they need to be monitored for diabetes. More importantly, even a single complication of prednisone, such as an opportunistic infection requiring a hospitalization, would have a cost similar or higher than that of IVIG. Therefore, future studies of the chronic use of IVIG in MG should include assessments of cost effectiveness.

Conclusion

So the current hope for IVIG in MG is that it will reduce or eliminate the need for prednisone. Plans are under way for a pilot study to look at exactly this. If successful this could lead to a significant shift in the standard management of MG, with more reliance upon intermittent treatments with IVIG and less reliance on prednisone. This will mean fewer side effects for MG patient and hopefully improved quality of life.


References

1) Dalakas MC. Intravenous Immunoglobulin In The Treatment Of Autoimmune Neuromuscular Diseases: Present Status And Practical Therapeutic Guidelines. Muscle Nerve 22: 1479-1497, 1999

2) Perez Nellar J. Dominguez AM. Llorens-Figueroa JA. Ferra-Betancourt A. Pardo A. Quiala M. Gali Z. A comparative study of intravenous immunoglobulin and plasmapheresis preoperatively in myasthenia]. [Spanish] Revista de Neurologia. 33(5):413-6, 2001 Sep 1-15.

3) Gajdos P. Chevret S. Toyka K. In
travenous immunoglobulin for myasthenia gravis. [Review] [39 refs] Cochrane Database of Systematic Reviews. (2):CD002277, 2003.

4) Achiron A. Barak Y. Miron S. Sarova-Pinhas I. Immunoglobulin treatment in refractory Myasthenia gravis. Muscle & Nerve. 23(4):551-5, 2000 Apr.

5) Wegner B. Ahmed I. Intravenous immunoglobulin monotherapy in long-term treatment of myasthenia gravis. Clinical Neurology & Neurosurgery. 105(1):3-8, 2002 Dec.

6) Wolfe GI. Barohn RJ. Foster BM. Jackson CE. Kissel JT. Day JW. Thornton CA. Nations SP. Bryan WW. Amato AA. Freimer ML. Parry GJ. Myasthenia Gravis-IVIG Study Group. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle & Nerve. 26(4):549-52, 2002 Oct.

7) Ferrero B. Durelli L. High-dose intravenous immunoglobulin G treatment of myasthenia gravis. [Review] [133 refs] Neurological Sciences. 23 Suppl 1:S9-24, 2002 Apr.

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