Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 2012, Kansas City, KS 66160, USA
*Corresponding author. ude.cmuk@eikhcamidm
Keywords: Myasthenia gravis, Pyridostigmine, Prednisone, Thymectomy, Immunotherapy, Complement inhibition, Intravenous immunoglobulin, Plasma exchange
Copyright notice
The publisher's final edited version of this article is available at Neurol Clin
INTRODUCTION
Myasthenia gravis [MG] is the most common acquired disorder of neuromuscular transmission. It occurs due to the production of pathogenic autoantibodies that bind to components of the neuromuscular junction, the most common being the acetylcholinesterase receptor [AChR]. The incidence is estimated at 0.3 to 2.8 per 100,000 and the worldwide prevalence at 700,000. In 1934, cholinesterase inhibition was demonstrated as the first effective treatment for MG. Until the last 20 years, most MG treatment was investigated through retrospective clinical studies. More recently, there have been a number of randomized controlled clinical trials []. The decades that various MG treatments were introduced is shown in . This development has been associated with dramatic improvements in survival and prognosis in MG. The primary reasons for reduced mortality rates are the improvement in intensive respiratory care and the introduction of immunosuppressive treatments. Although the mortality rate was previously quite high, resulting in the name MG, the current mortality rate in MG is reported as 0.06 to 0.89 per million person-years. The various treatments for MG and the approximate time lag to onset of action are outlined in Table 1.
Table 1
Summary and treatment recommendations for myasthenia gravis
TherapyStarting DoseMaintenance DoseOnset of
ActionAdverse EventsMonitoringCommentFirst-line therapies Pyridostigmine60 mg every 6 h while awake60–120 mg every 3–8 h while awake15–30 minLoose stools, n/v, diarrheaNonePatients can learn over time to adjust dosage; with current dosing, cholinergic crisis is rare PrednisoneRapid induction regimen: 60–100 mg/d for 2–4 wk; slow titration regimen: 10 mg/d, increase by 10 mg every 5–7 d up to 60–100 mg60–100 mg/d, followed by a slow alternate day taper2–4 wkHTN, hyperglycemia, fluid retention, weight gain, bone density loss, neuropsychiatricWeight, BP, glucose, potassium, bone density monitoringWith high doses, watch for early worsening. Seen in as many as half of patients; single morning dose; minimize long-term exposure Thymectomy——6–12 mo——See textSecond-line therapies Azathioprine50 mg, single morning doseIncrease by 50 mg every 2–4 wk; goal dose 2–3 mg/kg/d12–18 moFlu-like illness, n/v, hepatotoxicity; leukopeniaCBC, LFTs monthly. Weekly only for first monthMajor drug interaction with allopurinol; uncertain degree of fetal risk in pregnancy Cyclosporine100 mg twice dailyGoal dose 3–6 mg/kg/d, divided in 2 daily doses1–3 moNephrotoxicity, HTN, infection, hepatotoxicity, hirsutism, tremor, gum hyperplasia, neoplasiaBP, monthly cyclosporine trough level 100 mg/d] for 2 to 4 weeks. After this period, a decision is made to immediately switch to every other day or to continue daily high-dose therapy. Switching immediately to alternate day high-dose corticosteroids may be used for patients who are Myasthenia Gravis Foundation of America [MGFA] grade 2 [mild]. However, higher grade patients with MG usually require daily corticosteroid dosing for extended periods. Whether the patient is switched to a higher daily dosing at 2 to 4 weeks or left on high-dose daily therapy, the patient is usually kept on that dose [eg, 100 mg every other day or 50 mg/d] for another 4 to 8 weeks, at which time improvement should be noted and a slow taper by 5 to 10 mg a month can be initiated.
A low-dose and slow titration regimen is suited for patients with milder disability, including ocular MG or in mild to moderate MG. In the low-dose approach, 10 mg/d is administered, and the prednisone is increased by 10 mg every 5 to 7 days to a peak dose of 1.0 to 1.5 mg/kg/d [up to 60–100 mg]. A third and more recent approach is based on the mycophenolate mofetil study, and it places patients on a fixed dose of prednisone 20 mg immediately, monitoring that dose, unless there is no response, and then the dose should be increased. We have been using the 20 mg/d and stay approach since the mycophenolate mofetil study, and have found that it is often successful, as in the mycophenolate study. We believe that a comparative effectiveness study of different prednisone dosing approaches in MG is warranted.
Daily prednisone use is also the rule for patients in myasthenic crisis and for those with worsening symptoms but who are not yet in crisis. A switch to alternate day prednisone can be made months later, when the patient has begun to improve significantly. A daily long-term steroid regimen may be indicated in patients with diabetes and hypertension to avoid wide swings in serum glucose and blood pressure, respectively.
In ocular MG, the use of corticosteroids has been the subject of debate, weighing the considerable functional impairment from diplopia and ptosis against the risk of significant systemic toxicity from chronic corticosteroid use. A recent small randomized, double-blind trial of prednisone 10 mg every other day titrated up to 40 mg/d over 16 weeks versus placebo in patients with ocular MG showed that 100% of the placebo group patients [n = 5] failed to improve, whereas only 17% of the prednisone group [n = 6] failed to improve [P = .02]. The strength of this evidence is limited by a small sample size, but this study indicates that prednisone can be an effective treatment for ocular MG and should be considered in patients that fail acetylcholinesterase inhibitors. This small but dramatically positive study is probably the best randomized controlled trial of prednisone in MG.
Several retrospective studies have provided evidence that immunotherapy [including treatment with corticosteroids] may reduce the risk of developing generalized MG in patients with ocular MG., In the largest of these studies, after 2 years of follow-up, 36% of patients not treated on prednisone progressed to generalized MG versus only 7% of patients treated with prednisone. In another retrospective study, pyridostigmine was used without prednisone in 59 of 97 patients with ocular MG with 12 developing generalized MG, whereas none of the 38 prednisone-treated cases developed generalized MG.
The systemic side effects of long-term corticosteroid therapy are numerous and can be highly impactful. They include weight gain, diabetes, hypertension, eye disease [cataract and glaucoma], accelerated bone demineralization, and neuropsychiatric disturbances. Potential complications should be discussed before the initiation of treatment, and prevention and monitoring plans should be established in collaboration with the patient’s primary care physician. We recommend placing a tuberculin skin test or obtaining a QuantiFERON-TB Gold test to identify patients previously exposed to tuberculosis before starting corticosteroids therapy. Prophylactic therapy is indicated in those who test positive for prior exposure. Patients should be counseled about a low carbohydrate, low calorie, and low salt diet. If the patient is hospitalized, this can be done by the dietician. However, dieticians are often not available in the outpatient setting and, therefore, it is up to the neurologist to provide some dietary guidance. The advice of “no junk food/no salt when food gets to the table” is a good starting point, and should be reinforced on follow-up visits. A dual energy x-ray absorptiometry scan and an ophthalmologic examination should be obtained at baseline and repeated annually. Calcium [500 mg 2 to 3 times daily] and vitamin D [400 IU/d] supplements should be taken to reduce the risk of pathologic fractures. Patients should also remain up to date on all vaccinations, including the flu and pneumococcal vaccines, but no live or live attenuated vaccines should be used by patients on immunotherapy.
OTHER IMMUNOSUPPRESSANTS
Azathioprine
Azathioprine is a purine synthesis cytotoxic antimetabolite that inhibits DNA and RNA synthesis, cellular replication, and lymphocyte function. The use of azathioprine for MG therapy was pioneered in Europe in the 1970s, and azathioprine has become the most widely accepted steroid-sparing immunosuppressant used for MG., In comparison with other steroid-sparing options, azathioprine has more favorable tolerability, although a major challenge in its clinical use is the estimated 6- to 18-month latency between treatment initiation and therapeutic onset.,
A number of earlier retrospective studies have suggested response rates to azathioprine ranging from 70% to 91%., There has been 1 randomized, double-blind clinical trial of oral prednisolone plus azathioprine 2.5 mg/kg/d versus oral prednisolone and placebo. Enrollment was slow, took several years to complete it. Patients were observed over 3 years and the corticosteroid dose was adjusted up or down to the lowest dose necessary to maintain pharmacologic remission. Thirty-four patients were enrolled, but the dropout rate was high. At 12 months, there was no significant difference in the prednisolone dose between both groups [N = 24; placebo 15 cases and azathioprine 9], but there was a trend for a lower prednisolone dose in the azathioprine group. At 18 months, there was a statistically significant difference in the prednisolone dose between the 2 groups. At 3 years, most patients in the prednisolone plus azathioprine group [n = 8] had been successfully tapered off steroids. Weight gain was also less in the prednisolone plus azathioprine group compared with the prednisolone and placebo group, at 2 kg/y and 5.8 kg/y, respectively. Conversely, in the prednisolone and placebo groups, patients were more likely to fail to remit and to relapse even with the flaws noted. This is an important positive study in the MG field and supports the use of azathioprine. However, azathioprine may not improve an MG patient in the first year of treatment and is used for long-term management to get patients on lower corticosteroids doses or off corticosteroids altogether.
Azathioprine has been used in patients with generalized MG on corticosteroids who are still symptomatic; in patients with relative contraindications to corticosteroids treatment such as hypertension, diabetes, and osteoporosis; and in those who experience severe side effects to corticosteroids. Azathioprine has also been used in patients with ocular MG requiring but not tolerating corticosteroid therapy.
The starting dose for azathioprine is 50 mg/d [see Table 1]. Dosing can be increased in 50-mg increments every 2 to 4 weeks to a goal dose of 2 to 3 mg/kg/d. Blood counts and liver function should be tested at baseline, and then monthly. An important monitoring parameter of bone marrow suppression is the white blood count and leukopenia. Others include liver function test evaluation [alanine aminotransferase, aspartate aminotransferase]. We monitor a complete blood count and a complete metabolic panel. If the white blood cell count decreases to less than 4000 mm3, we decrease the azathioprine dose, and if it decreases to less than 3000 per mm3, we stop the drug. We also monitor the absolute neutrophil count to make sure it is not affected, but expect some lymphopenia in the range of 500 to 1000 per mm3. If the aspartate aminotransferase or alanine aminotransferase levels elevate, we stop the drug. When the liver enzymes return to normal the patient can be rechallenged and occasionally this measure can be effective without enzyme elevations.
In rheumatic diseases and in posttransplant care, azathioprine has been linked to a higher risk of developing a malignancy, although a parallel phenomenon has not been described in patients with MG. Although evidence from the transplant literature indicates that the risk for adverse outcomes from azathioprine use in pregnancy is very low, we do not use azathioprine in pregnancy.
Of the patients placed on azathioprine, 10% to 20% have an idiosyncratic drug reaction presenting as a flulike syndrome with fever, malaise, and loss of appetite. This phenomenon occurs in the first 1 to 2 weeks after starting the drug. If it occurs, azathioprine should be stopped immediately, and the symptoms will lessen in a day or two. If azathioprine is restarted, these side effects almost always recur.
It has been suggested that before initiation of azathioprine, thiopurine methyltransferase phenotype or genotype be tested as an inherited enzyme deficiency predicts an increased risk for leukopenia. A systematic review of 55 studies found that, although diminished TMPT activity is associated with myelotoxicity, there is insufficient evidence to support screening patients for thiopurine methyltransferase deficiency. In practice, we monitor blood cell counts closely instead.
Mycophenolate Mofetil
Similar to other newer immunosuppressants, mycophenolate mofetil was introduced in neuromuscular diseases after initial experience as an antirejection drug in transplant medicine. Mycophenolate mofetil is a potent monophosphate dehydrogenase inhibitor. It inhibits guanosine nucleotide synthesis that is essential for B and T lymphocytes. Initial interest was spurred in MG after the report of a patient with treatment-refractory early-onset myasthenia who had a rapid response to mycophenolate mofetil. Several retrospective studies suggested a favorable tolerability profile, the potential for a prednisone-sparing effect, and robust rates of disease control around 70%., In addition, in comparison with azathioprine, a more rapid initial clinical response time [11 weeks] was suggested.
However, both of 2 large multicenter, randomized, double-blinded, placebo-controlled trials failed to show that mycophenolate mofetil in addition to prednisone was more effective in controlling MG. In 1 study, 80 patients with mild to moderate generalized AChR antibody–positive MG were randomized to 20 mg/d of prednisone plus 2.5 g/d mycophenolate mofetil versus 20 mg/d prednisone and placebo and followed over 12 weeks. The primary outcome was change in the Quantitative Myasthenia Gravis [QMG] score, which was similarly decreased in both groups, indicating there was no advantage detected in the mycophenolate mofetil group. Both groups improved which implies a significant effect of prednisone 20 mg/d. In the international phase III mycophenolate mofetil study, 176 AChR antibody–positive patients with mild to moderate MG who were already taking corticosteroids were randomized to mycophenolate mofetil 2 g/d versus placebo. At the conclusion of 36 weeks [9 months], the primary endpoint measured — which was a composite of a favorable MGFA postintervention status and prednisone and pyridostigmine doses below certain preset ceiling levels—did not show the mycophenolate mofetil group outperforming the placebo group.
The discordance between the retrospective and randomized trial data of mycophenolate mofetil has several potential explanations. The most favored is that the therapeutic potency of 20 mg of prednisone may have been underestimated and thus overwhelmed the therapeutic effect of mycophenolate mofetil. It is also possible that clinical trial periods were not long enough to capture the onset of the effect of mycophenolate mofetil, or that the disease population studied was too mildly affected to require both prednisone and mycophenolate mofetil for treatment. Since the publication of these negative randomized, controlled trials, another retrospective study provided evidence of benefit for mycophenolate mofetil, although the strength of the evidence is limited by its retrospective design. Despite 2 negative studies, mycophenolate mofetil is listed as part of the international consensus guidance for MG management. In our practice, although we still use mycophenolate mofetil for some patients with MG, we do not use it quite as often since the publication of these 2 randomized controlled trials. The most common regimens used are 1000 to 1500 mg twice daily [see Table 1]. The main side effects are diarrhea, nausea, infections, and leukopenia. Blood counts should be monitored closely at the initiation of treatment and thereafter monthly, and we use the same guidelines for dosing adjustment outlined for azathioprine. Mycophenolate mofetil is contraindicated in pregnancy owing to teratogenic potential and a higher risk of miscarriage in the first 3 months. Concerns exist regarding a potential increase in the risk of lymphoproliferative disease based on isolated case reports.,
Cyclosporine
Cyclosporine, an agent first used to suppress allograft rejection, interferes with calcineurin signaling, suppresses cytokine secretion including interleukin-2 and interferon-γ, and interferes with T-helper cell activation. Cyclosporine was the first immunosuppressant medication shown to be effective in the treatment of generalized MG in 2 small double-blind, randomized, controlled trials.,
In the first randomized trial, newly diagnosed, thymectomy- and immunosuppression-naïve generalized patients with MG were treated with cyclosporine 6 mg/kg/d versus placebo. The cyclosporine level was monitored, and the dose adjusted to maintain trough levels between 400 and 600 ng/mL and creatinine at 2.0 mg/dL or less. At 6 months, the cyclosporine group had a lower QMG score compared with the placebo group, and that persisted and remained statistically significant at 12 months. In a second randomized, controlled trial of cyclosporine, a group of steroid-dependent patients [≥30 mg of prednisone every other day] with or without a thymectomy, and with varying degrees of prior immunosuppressive therapy was treated with 5 mg/kg/d of cyclosporine versus placebo with the cyclosporine dose adjusted to maintain trough levels between 300 and 500 ng/mL and creatinine of 2.0 mg/dL or less. At the conclusion of the study at 6 months, the cyclosporine group had a lower QMG score, had a greater reduction of AChR antibody levels, and was on a lower prednisone dose, although this lower dose was not statistically significant. In an 18-month, open-label extension of the study, the steroid-sparing effect of cyclosporine seemed to increase.
Acute and more indolently progressive renal toxicity and hypertension are major factors limiting the tolerability of cyclosporine. Serum creatinine levels in a case series increased by a mean of 48% in more than one-quarter of treated patients and the cumulative side effects led to the discontinuation of treatment in 35% of patients over a 2-year period., There is also evidence that cyclosporine is associated with increased dermatologic and other malignancy risk. In addition to increased skin surveillance and measures to limit sun exposure, the neoplasia risk of cyclosporine should be reviewed individually before initiating treatment. Other limiting side effects are hirsutism, tremor, gum hyperplasia, paresthesias, headaches, and hepatotoxicity.
The starting dose of cyclosporine is usually 3 mg/kg/d [see Table 1] and it comes in 100 mg capsules. Thus, a 70-kg person generally takes 200 mg split in 2 doses. Similar to corticosteroids, the goal is to reduce cyclosporine to the lowest dose that maintains treatment effect. Trough levels should be monitored [keep at