By Jonathan Katz, M.D., director, Neuromuscular Program,Forbes Norris MDA/ALS Research and Treatment Center
The most complex part of treating patients with myasthenia gravis (MG) is juggling a large number of potentially effective therapies. Clinical trials are difficult for a variety of reasons and as a result, most treatments lack a firm evidence basis. Recruitment is challenging as many MG cases tend to be either too mild to study or so severe that studies that withhold therapy could put them at risk. It is also important to note prednisone is widely used to treat MG, and puts most patients in or near remission. Still, interesting studies continue to shed light on pathophysiology and management options.
Muscle-Specific Tyrosine Kinease Myasthenia Gravis
We continue to learn more about muscle-specific tyrosine kinase myasthenia gravis (MuSK-MG). A large cohort found this condition has a marked female predominance with frequent oculobulbar weakness (1), accompanied by a relatively high incidence of crises, with many patients deteriorating rapidly early in the disease. Plasma exchange
(PLEX) is now considered the preferred treatment for these difficult cases. Long-term outcomes are similar to those of patients with acetylcholine receptor (AChR)-related MG. Our understanding of how MuSK antibodies affect the neuromuscular junction has changed over the past year. MuSK was initially described as a protein playing a role in organizing postsynaptic neuromuscular junctions, primarily by responding to signals, originating from nerve, to sequester acetylcholine receptors in one spot, thus forming a junction.
But a new report finds that MuSK also functions in anchoring extracellular acetylcholine esterase to the postsynaptic basal membrane (2). The report found that it was this pathway that was involved in four patients with the disease. This would potentially help explain what is felt to be a poor response to AChR inhibitors. These studies remind us that while the two types of MG present with similar clinical features, the underlying diseases are different. For example, MG with thymoma is not seen in MuSK, but AChR antibodies occur in virtually all cases. Again, we should be cautious with our assumptions that treatment for one can apply to the other.
Two reports have now lent support for Rituxan in refractory MG. In one, Nowak et al4 found that rituximab is beneficial and well tolerated in managing either MuSK or AChR-related MG. A second report by Diaz-Manera et al (3) found similar results, although it added that Rituxan may be more useful in MuSK-related MG. After a mean of 31 months after infusion, 10/16 AChR-related patients improved, while six needed reinfusions. In contrast, all six MuSKrelated patients improved, with four achieving remission. In both studies, prednisone and concomitant immunosuppressants could be reduced, and antibody titers fell. These articles were part of an overall stream of reports on Rituxan in MG.
There were a number of reports on other agents. One small trial compared the monoclonal, terminal complement inhibitor Eculizumab to placebo in severe, refractory MG; 6/7 treated patients had moderate improvement over 16 weeks, versus only 4/7 placebo. The result is hopeful, but further studies are needed to determine its role, and the therapy is costly. Another report of an MG therapy was noteworthy simply because it was published (5); two patients with relatively mild MG were managed with prednisone alone for nearly 20 years, without other immunosuppressive treatments or thymectomy. It reminds us that MG may be easy to control, and often goes into long remissions. Some patients may tolerate prednisone and use it sparingly for remissions or maintenance. The benefit of prednisone was also evident in other trials. For example, a key study of CellCept® and prednisone versus prednisone alone could not prove that CellCept worked. The reason was likely partially due to the relatively mild immunosuppressant action of CellCept, and that so many patients improved in both arms from the steroid that the trial was underpowered to detect smaller differences.
Evidence-Based Practice Parameter
By concluding the evidence was “Level U,” signifying insufficient evidence to support or refute the use of the procedure, an evidence-based American Academy of Neurology (AAN) practice parameter in MG raised the alarm that plasmapheresis did not meet the level of evidence required for a recommendation (6). It is important that clinicians recognize the meaning of these evidence-based assessments. They are derived from strict rules that aim to formulate a conclusion only about the body of work, but not necessarily the procedure itself. Here, lack of efficacy evidence is not evidence of a lack of efficacy. The report led to some concern about the guideline itself, but the one potential interpretation would be that, at the current time, only “non-evidence” based medicine can help us decide the right thing to do. There is no doubt that we have all observed MG patients improve with pheresis, but the practice parameter just reminded us that more studies are needed to establish efficacy. It is also worth noting that a randomized study was reported in the months after the release of the practice parameters, and found that intravenous human immunoglobulin (IVIg) is about as effective as PLEX in refractory MG (7).
One rather unique report described 19-year-old identical twins who developed MG within two months (8). One twin elected to undergo thymectomy and has been in remission for 12 years, while the other refused all therapies and has had ongoing ptosis and weakness. A large randomized, multicenter clinical trial of thymectomy in MG is under way (9). This study will almost certainly help resolve the long-standing debate about its effectiveness. As of January 2012, the worldwide, eight-year effort has recruited 115 subjects, but 35 more are still needed for completion. Each subject also needs to be observed for three years past enrollment. One wonders why the leaders in the field of MG are more willing to express uncertainty about thymectomy than about pheresis, given that imperfect evidence is a common feature of both. The answer to this interesting philosophical question probably has something to do with our ability to see an immediate benefit in PLEX, where we become apt to believe in what we see. This can be compared to drawing conclusions by observing long-term outcomes in a disease that has a fluctuating course, which is the case for thymectomy.
The questions about treatments and evidence were also filtered down in a very interesting study of the annual health care expenditures for MG in the U.S.(10) By reviewing a large health care database, the authors found that MG treatment costs roughly $25,000 per patient per year. For perspective, this was higher than annual expenditures for MS, Alzheimer’s disease, or migraine. Not surprisingly, the underlying price tag mainly reflected the increasing use of IVIg, and in particular, it came from a small number of patients receiving recurrent infusions. Pharmacy-related costs made up about 43% of overall expenditures, and while only 12% of patients received IVIg, it made up 85% of the pharmacy costs. Overall usage was also probably underestimated since hospital-based infusions of IVIg could not be ascertained. Nonsteroidal immunosuppressants counted for 9%, acetylcholine esterase inhibitors for 5%, and prednisone for just 0.2%. While evidence has suggested that IVig can benefit MG, this report raised key questions about gaps in evidence. Appropriate doses, intervals, and risks of relapse in chronic treatment remain unclear.
Thus, many treatments are available for MG. The evidence base is enlarging, but there is still both an art and a science to managing patients with this disease.
- Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve. 2011 Jul;44(1):36-40
- Kawakami Y, Ito M, Hirayama M, et al. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. Neurology 2011; 77: 1819–1826
- Díaz-Manera J, Martínez-Hernández E, et al. Longlasting treatment effect of rituximab in MuSK myasthenia. Neurology. 2012 Jan 4.
- Nowak RJ, Dicapua DB, Zebardast N, Goldstein JM. Response of patients with refractory myasthenia gravis to rituximab: a retrospective study. Ther Adv Neurol Disord. 2011 Sep;4(5):259-66
- Kataoka H, Furiya Y, Ueno S. Complete Remission of Generalized Myasthenia Gravis by Corticosteroid Treatment Alone without Thymectomy. Case Rep Neurol.2011 Sep;3(3):239-41. Epub 2011 Oct 3.
- Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: Use of plasmapheresis in neurologic disorders: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011; 76: 294–300
- Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011 Jun 7;76(23):2017-23.
- Riggs KR, Gutmann L, Riggs JE. Discordant thymectomy in identical twins concordant for myasthenia gravis. Ann Intern Med. 2011 Oct 4;155(7):478-9.
- Wolfe GI, Kaminski HJ, Jaretzki A 3rd, Swan A, Newsom-Davis J. Development of a thymectomy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressive therapy. Ann N Y Acad Sci. 2003;998:473-80
- Guptill JT, Marano A, Krueger A, Sanders DB. Cost analysis of myasthenia gravis from a large U.S. insurance database. Muscle Nerve. 2011 Dec;44(6):907-11
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