Director, Neurology Neuromuscular Residency Program, Thomas Jefferson University

Ericka Wong, MD

autoimmune disorder caused by the presence of autoantibodies against the neuromuscular junction, which results in fatigable weakness. Chronic immunosuppression is among the mainstays of long-term therapy in MG. This article offers a practical approach to initiating and tapering corticosteroids, in addition to reviewing some of the considerations in the selection and monitoring parameters of steroid-sparing agents. We will also briefly introduce some novel therapies for MG.

Per international consensus, corticosteroids (specifically prednisone) comprise first-line immunosuppressive therapy for all patients who have not achieved disease control with pyridostigmine.

 Efficacy trials have shown marked improvement (45%) or remission (30%) in most MG patients initiated on corticosteroids.

There are 2 treatment approaches to the initiation of corticosteroids, and the choice of approach is dependent upon the patient’s level of disability at presentation. The low-dose, slow-titration approach is generally appropriate for patients with mild-to-moderate generalized or ocular disease. This regimen is less likely to produce the paradoxical worsening that can be seen within the first 3 weeks in up to half of patients started on steroids.

 The high-dose, rapid-induction approach is considered for patients with impending myasthenic crisis or severe disability due to a faster onset of action.

 In these cases, the risk of paradoxical worsening from steroids is usually offset by simultaneous administration of either intravenous immunoglobulin (Ig) or plasmapheresis.

The high-dose treatment regimen involves initiation of prednisone at a dose of 1.5 mg/kg/day (up to 100 mg per day) for 2 to 4 weeks.

 After this, the patient can either be transitioned to a high daily dosing or alternate-day dosing routine; for example, the patient can either be started on 50 mg daily or 100 mg every other day. The high daily dosing or alternate-day dosing is maintained until a plateau has been reached in clinical improvement for at least 4 weeks.

 A slow taper can then be introduced, decreasing by 10 mg every 4 weeks until the patient is on 20 mg daily. Once the patient is on 20 mg daily, tapering is commonly slowed to decrease by increments of 5 mg every month. Below 10 mg daily, an even slower taper (1.0-2.5 mg every 2-4 weeks) is often necessary to prevent relapse of symptoms.

The low-dose, slow-titration schedule starts the patient on 10 to 20 mg of prednisone per day, with an increase of 10 mg every 1 to 2 weeks up to 1 to 1.5 mg/kg/day (no more than 60-100 mg daily).

 Again, the higher dose is maintained until the patient has been stable for at least 4 weeks, and then the patient is slowly tapered as described above. If a patient experiences relapse in symptoms during a taper, the dose of steroids is increased again to the lowest effective dose.

Chronic, continual corticosteroid use is associated with increased susceptibility to infection, diabetes, weight gain, osteoporosis, steroid myopathy and aseptic necrosis of the joints.

 Prior to initiating steroids, patients should be screened for tuberculosis (TB), and those with a history of TB may need to be prophylactically treated. Monitoring of bone density with a dual-energy X-ray absorptiometry (DEXA) scan at baseline and at 6 to 12 months after steroid initiation can be considered, and patients should be prophylactically started on calcium and vitamin D supplements to prevent osteoporosis.

 Bisphosphonates may be initiated for postmenopausal women or for patients who have evidence of osteopenia or osteoporosis on their DEXA scans. Blood glucose should also be monitored carefully while patients are maintained on steroids, particularly when they are on higher doses.

Due to the myriad of complications that result from chronic corticosteroid use, the objective is to taper patients down to the lowest effective steroid dose without causing recurrence of symptoms. Alternate “steroid-sparing” immunosuppressive agents are added with the goal of reducing the daily steroid dose or discontinuing steroids altogether. They may be started simultaneously with prednisone in patients with severe disease due to their delay in onset of action; they can also be started later on if a patient is unable to taper to low-dose prednisone (often accepted to be 10 mg or less daily) without relapsing. Once a patient has remained stable for 6 to 12 months on a steroid-sparing agent, prednisone can be gradually tapered as previously described.

 In patients with diabetes or osteopenia, steroid-sparing agents can be considered as first-line treatment to avoid the adverse effects (AEs) of steroids.

Various classes of steroid-sparing immunosuppressants are used to treat MG: antimetabolites (eg, azathioprine, mycophenolate mofetil, methotrexate), calcineurin inhibitors (eg, cyclosporine), monoclonal antibodies (eg, rituximab), complement inhibitors (eg, eculizumab, ravulizumab), and the upcoming FcRn antagonists.

Azathioprine is the most frequently utilized steroid-sparing immunosuppressant in MG and currently has the best efficacy data. A double-blind, placebo-controlled study randomized patients into groups receiving azathioprine + prednisolone or placebo + prednisolone, and approximately 60% of the azathioprine group did not require retreatment with steroids after 36 months.

 Azathioprine is typically initiated at 50 mg daily and increased by increments of 50 mg every 2 to 4 weeks to a goal of 2 to 3 mg/ kg/day.

 Some patients experience a flu-like illness that can contribute to early intolerance of the medication. Complications can include bone marrow suppression, hepatic toxicity, pancreatitis, and teratogenicity.

 To monitor for these AEs, a complete blood count (CBC) and a hepatic panel should be obtained at baseline and then monitored closely, particularly in the first few months. Screening for deficiency of the enzyme thiopurine methyltransferase, which predisposes patients to bone marrow toxicity in those exposed to azathioprine, is often performed, although the benefit is unclear. Leukopenia is a good indicator of bone marrow suppression, and it can be seen as early as 1 to 2 weeks after initiation.

 The dose should be decreased if the white blood cell (WBC) count is less than 4000/mm

, and azathioprine should be held if the WBC count is less than 2500/mm

 or the absolute neutrophil count is less than 1000 mm3.

 Hepatotoxicity can be observed within the first several months, and azathioprine should be discontinued if transaminases increase by more than 2 to 3 times the initial levels.

 Other practical considerations include the avoidance of allopurinol due to its interference with the metabolism of azathioprine.2 In addition to other AEs, a limitation of the use of azathioprine is the delayed onset of action of approximately 6 months; the full benefit may not be seen until as long as 12 to 18 months after the agent is started.

The use of mycophenolate mofetil (MMF) is not supported by evidence from clinical trials but is used in MG based on clinicians’ observational experience. Its ease of use and tolerability are also attractive. MMF showed reported benefit in a few observational studies and open-label trials, but 2 double-blind placebo-controlled studies did not show a significant difference between MMF + prednisone vs placebo + prednisone.

 Typical dosing for MMF consists of 1000 to 2000 mg per day divided into 2 doses. Clinical improvement is most often observed within the first 3 months but can be delayed up to 1 year after initiation.

 Leukopenia is a significant AE; other common AEs include diarrhea, nausea, and infections. A CBC should be obtained at baseline and then closely monitored. MMF is teratogenic and contraindicated in pregnancy.

Evidence for the benefit of methotrexate (MTX) in MG is limited, but it may be considered for patients who have not responded to other steroid-sparing agents.

 It also has the advantage of an earlier onset of action compared with azathioprine. It is started at 7.5 mg per week (divided into 3 doses given 12 hours apart) and increased by 2.5 mg every 1 to 2 weeks up to 20 to 25 mg per week.

 MTX can cause AEs including stomatitis, bone marrow suppression, interstitial lung disease, pulmonary fibrosis, renal toxicity, and liver toxicity.

 Patients should be started on folic acid to mitigate these AEs. Due to teratogenicity, MTX is contraindicated in women who may become pregnant; it should also be used in caution with patients with lung disease.

 CBC and hepatic panels should be monitored closely.

Cyclosporine has been shown to be effective in the treatment of MG but is rarely chosen as a first-line agent due to its AE profile and monitoring parameters. Its main advantage over azathioprine is its quicker onset of action, with improvement typically seen within 2 to 3 months of initiation.

 The most notable AE is nephrotoxicity, which can be seen in approximately a quarter of patients and can occur in both the acute setting and in a delayed fashion.

 Serum creatinine needs to be monitored monthly after initiation, and the dose should be decreased with any significant elevation in creatinine. Trough cyclosporine levels should also be monitored. Other AEs include hypertension, tremor, liver toxicity, hirsutism, paresthesias, and headache.

 Cyclosporine is initiated at a dose of 3 mg/kg/day divided into 2 doses and gradually increased to a maximum of 6 mg/kg/day.

Rituximab is a CD20 monoclonal antibody with favorable evidence from case series for its use in both anti-AChR and anti-MuSK MG, and it should be considered early on for anti-MuSK MG that has not responded to initial immunotherapy.

 infusions given weekly for 4 weeks. Another frequently used method is administering 1 g/m

 twice, 2 weeks apart. The frequency of redosing is dependent on the patient’s clinical response; response can be seen as early as 4 to 6 months or as late as 24 months after initiation. Before initiating rituximab, patients should obtain a baseline CBC and be screened for hepatitis B due to the risk of reactivation. Possible AEs also include leukopenia, anemia, and thrombocytopenia. An uncommon but potential complication is the development of progressive multifocal encephalopathy.

Complement inhibitors interfere with the autoimmune pathway, which results in endplate destruction.

 These medications are not effective in anti-MuSK MG because the MuSK autoantibodies do not activate the complement cascade.

 Eculizumab is a humanized monoclonal antibody against complement protein C5, and it can be considered for refractory anti-AChR MG.

 A randomized, placebo-controlled trial demonstrated benefit in refractory MG with a significant reduction in quantitative MG score.

 In a phase 3 trial, patients were given an induction dose of 900 mg/week for 4 doses, followed by a maintenance dose of 1200 mg every 2 weeks; benefit was demonstrated over the placebo group but it did not reach statistical significance.4 The most serious AE with administration of this drug is the increased risk of 

infection, so patients should be vaccinated prior to treatment.

Zilucoplan is a synthetic peptide that binds to complement protein C5 at a different binding site compared with eculizumab, so it may be considered in the future for patients with C5 mutations who do not respond to eculizumab.

 A phase 3 trial of zilucoplan is currently ongoing and will include nonrefractory MG patients. Ravulizumab is a monoclonal humanized antibody that also binds to complement protein C5 but has a longer half-life compared with eculizumab and can be administered every 8 weeks.

 A phase 3 trial of ravulizumab is currently ongoing.

The FcRN antagonists comprise a novel class of medications in the treatment of MG; they aim to interfere with the recycling of autoantibodies in the process of lysosomal degradation.

 Efgartigimod is a humanized IgG1-derived Fc fragment that was given in 4 infusions over 3 weeks in a double-blind, placebo-controlled trial to patients with anti-AChR MG. The study showed a decrease in IgG serum concentration by 50% by week 3 and a statistically significant reduction of quantitative MG scores after the first infusion.

 A multicenter, randomized, placebo-controlled, phase 3 trial was recently completed, finding that efgartigimod was well tolerated and efficacious in patients with generalized MG.

Rozanolixizumab is a humanized IgG4 monoclonal antibody that was given as a subcutaneous infusion once weekly for 6 weeks in a randomized, subject-blind, placebo-controlled trial in patients with anti-AChR MG. The study demonstrated improvement in all clinical scores compared with placebo without reaching statistical significance, but improvement in the MG-Activities of Daily Living score was statistically higher in the treatment arm compared with placebo.

Chronic immunosuppressive therapy in MG can provide long-term stability for many patients. For patients who continue to be refractory or are unable to tolerate current medication options due to AEs, emerging novel therapies with more targeted immunosuppression may offer alternatives in the near future.

REFERENCES
1. Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87(4):419-425. doi:10.1212/WNL.0000000000002790
2. Amato AA, Russell JA. Neuromuscular Disorders. McGraw-Hill Medical; 2008.
3. Farmakidis C, Pasnoor M, Dimachkie MM, Barohn RJ. Treatment of myasthenia gravis. 

Neurol Clin. 2018;36(2):311-337. doi:10.1016/j.ncl.2018.01.011
4. Lascano AM, Lalive PH. Update in immunosuppressive therapy of myasthenia gravis. Autoimmune Rev

. 2021;20(1):102712. doi:10.1016/j.autrev.2020.102712
5. Narayanaswami P, Sanders DB, Wolfe G, et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-122. doi:10.1212/WNL.0000000000011124
6. Howard JF Jr, Bril V, Vu T, et al; ADAPT Investigator Study Group. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. 

Lancet Neurol. 2021;20(7):526-536. doi:10.1016/ S1474-4422(21)00159-9

Articles

A practical approach to initiating and tapering corticosteroids, and the considerations in the selection and monitoring parameters of steroid-sparing
agents are crucial to the care of myasthenia gravis.

Ericka Wong, MD

Articles

A Practical Approach to Chronic Immunosuppression in Myasthenia Gravis

Latest News