Myasthenia gravis: Newer therapies offer sustained improvement
ABSTRACTMyasthenia gravis is a prototypical antibody-mediated autoimmune neuromuscular disorder. Treatments have improved over the past 30 years, leading to significantly fewer deaths and better quality of life. Future research should further elucidate its pathogenesis, reveal better ways to diagnose it, and yield new treatments.
KEY POINTS
- In most cases of myasthenia gravis, the patient has antibodies against acetylcholine receptor (AChR) or musclespecific tyrosine kinase (MuSK).
- Myasthenia gravis is diagnosed by clinical signs, bedside tests (the ice-pack test or the edrophonium test), serologic tests for AChR antibodies or MuSK antibodies, and electrophysiologic tests.
- Acetylcholinesterase inhibitors are the first-step therapy, but patients who have moderate to severe symptoms require some form of immunomodulating therapy.
- A number of drugs can exacerbate weakness in myasthenia gravis and should be avoided or used with caution. These include penicillamine, interferons, procainamide, quinidine, and antibiotics such as quinolones and aminoglycosides.
Mycophenolate mofetil
A well-tolerated medication with few side effects, mycophenolate mofetil is being used more in myasthenia gravis. The results of two recent randomized trials suggested that it is not effective in improving myasthenia gravis symptoms or sparing prednisone dosage when used for 90 days or 36 weeks.42,43 However, extensive clinical experience supports its longterm efficacy in myasthenia gravis.
In a retrospective study of 85 patients with generalized myasthenia gravis, mycophenolate at doses of 1 to 3 g daily improved symptoms in 73% and produced remission in 50%. Steroid dosage was reduced in 71% of patients.44
Another retrospective study, with 102 patients, verified a slow development of clinical benefit after months of mycophenolate therapy alone or in combination with prednisone. Approximately 50% of patients achieved a minimal manifestation status after 6 to 12 months of mycophenolate treatment. Eventually, at 24 months of treatment, 80% of patients had a desirable outcome of minimal clinical manifestation or better, 55% of patients were able to come off prednisone entirely, and 75% were taking less than 7.5 mg of prednisone per day.45
Common side effects of mycophenolate include nausea, diarrhea, and infections such as urinary tract infections and herpes reactivation. The complete blood cell count needs to be monitored frequently during the first 6 months of therapy. Leukopenia can occur but rarely necessitates stopping mycophenolate. Long-term safety data are lacking, but so far there has been no clearly increased risk of malignancy.
Mycophenolate exposure in pregnancy results in a high incidence of major fetal malformations. Therefore, its use in pregnant patients is discouraged, and women of child-bearing age should use effective contraception.46
Cyclosporine
A randomized trial in a small number of patients suggested that cyclosporine is fairly effective as monotherapy.47 Its onset of action in myasthenia gravis is faster than that of other corticosteroid-sparing agents, and clinical benefit can often be observed as early as 1 to 2 months. A dose of 5 mg/kg/day and a maintenance serum level of 100 to 150 ng/mL are generally recommended. However, renal, hepatic, and hematologic toxicities and interactions with other medications make cyclosporine a less attractive choice.
Methotrexate
A randomized trial evaluated the utility of methotrexate as a steroid-sparing agent compared with azathioprine.48 At 24 months, its steroid-sparing effect was similar to that of azathioprine, and the prednisone dosage had been reduced in more than 50% of patients.
Another phase II trial studying the efficacy of methotrexate in myasthenia gravis is under way.49
Rituximab
Rituximab is a monoclonal antibody against B-cell membrane marker CD20. A growing number of case series support its efficacy in patients with severe generalized myasthenia gravis refractory to multiple immunosuppressants.16,50 It seems particularly effective for MuSK antibody-positive disease, reducing MuSK antibody titers and having a treatment effect that lasts for years.
The standard dosage is 375 mg/m2 per week for 4 consecutive weeks. Peripheral B cells tend to be depleted within 2 weeks after the first infusion, while T-cell populations remain unchanged.50
A minimal infusion reaction such as flushing and chills can be seen with the first infusion. Patients may be more susceptible to certain infections such as reactivation of herpes zoster, but overall rituximab is well tolerated. Rare cases of progressive multifocal leukoencephalopathy have been reported in patients taking it, but none have occurred so far in myasthenia gravis treatment.
Cyclophosphamide
Cyclophosphamide is an alkylating agent that reduces proliferation of both B and T cells. It can be effective in myasthenia gravis, but potentially serious side effects limit its use. It should be reserved for the small percentage of cases that are refractory to other immunotherapies.
Thymectomy
Surgical treatment should be considered for patients with thymoma. If the tumor cannot be surgically resected, chemoradiotherapy can be considered for relief of myasthenic symptoms and for prevention of local invasion.
Thymomas recur in a minority of patients many years after the initial resection, sometimes without myasthenia gravis symptoms. A recurrence of symptoms does not necessarily indicate a recurrence of thymoma. The lack of correlation between myasthenia gravis symptoms and thymoma recurrence highlights the importance of radiologic follow-up in these patients.
For patients without thymoma, many experts believe that thymectomy is beneficial in patients under age 60 who have generalized myasthenia gravis. The likelihood of medication-free remission is about twice as high, and the likelihood of becoming asymptomatic is about one and a half times higher after thymectomy.51 However, it takes up to several years for the benefits of thymectomy to manifest, and thymectomy does not guarantee protection from developing AChR antibody-positive myasthenia gravis in the future.
The optimal timing of thymectomy is not well established; however, the procedure is usually recommended within the first 3 years of diagnosis.52 The response rates from thymectomy are similar for AChR antibody-positive and seronegative patients. In general, thymectomy for MuSK antibody-positive patients has not been effective, and its role in ocular myasthenia gravis is unclear.2,53
