Azathioprine and other immunosuppressive drugs Azathioprine is a useful adjunct to steroids in patients who cannot tolerate or fail to respond to prednisone. It has been possible to manage the disease reasonably well in a few of patients with azathioprine alone, but there is no study to support this practice (see Palace et al, 1998). Treatment typically begins with 50 mg (1 tablet) bid for a few days; if this is tolerated, the dosage is raised to 2 to 3 mg/kg/d (150 to 250 mg daily). However, improvement occurs much more slowly than with corticosteroids and a significant response may not be evident for many months to a year (Witte et al). Liver function tests and blood cell count should be checked regularly. The Myasthenia Gravis Clinical Study Group found that the most severe forms of the disease, particularly those resistant to either prednisone or azathioprine alone, benefit from the combination of the two medications. Azathioprine is a prodrug of mercaptopurine, which is metabolized principally by thiopurine methyltransferase (TPMT). Approximately 3 per 100,000 persons are deficient in the enzyme, for which reason, some clinicians measure its level before initiating azathioprine in order to avoid bone marrow toxicity; it has not been our practice to do so. There are many variant alleles of TPMT and a larger number of patients have partial deficiency of the enzyme or even excessive enzyme activity but it has not been clear how to utilize this information in myasthenia. Azathioprine interacts with other drugs such as allopurinol and warfarin.
Cyclosporine is another immunosuppressive drug that has shown benefit in clinical trials (Tindall et al). It is given in 2 divided doses daily, to a total of 6 mg/kg, but not often used currently because of serious side effects (hypertension, nephrotoxicity) and its high cost. Because of the success of alternative regimens, we have had occasion over the years to use cyclosporine only once for myasthenia.
Mycophenolate is currently being used as an adjunct to corticosteroids and has been beneficial in several small trials but failed to demonstrate similar effect in larger controlled studies. The clinical improvement, when it does occur, has generally occurred sooner than it does with azathioprine (Meriggioli et al). Diarrhea was the main adverse effect. Several experts in the field believe that mycophenolate is preferable to most of the adjunctive medications and in some milder cases may be effective alone, but reconciling this view with recent failed trials is vexing.
De Feo and coworkers have used cyclophosphamide administered in intravenous pulses; they were able to remove 5 of their 12 patients from steroids, but the appropriate use of this potent agent is not clear and we have resorted to it infrequently. Drachman and colleagues (2003), as well as others, describe a regimen of high-dose cyclophosphamide (50 mg/kg/d for 4 consecutive days) followed by granulocyte-stimulating factor to “reboot” the immune system in refractory cases. This approach has risks but may be justified if all other measures have failed. Liver function and white blood cell count require monitoring. On the basis of pilot trials, many other drugs, for example, tacrolimus as reported by Ponseti and colleagues, rituximab, and etanercept have come into use in patients who are dependent on or resistant to corticosteroids, including those with antibodies to MuSK (Diaz-Manera et al).