International consensus guidance in the management of MG
Symptomatic and IS treatment of MG.
- 1. Pyridostigmine should be part of the initial treatment in most patients with MG. Pyridostigmine dose should be adjusted as needed based on symptoms. The ability to discontinue pyridostigmine can be an indicator that the patient has met treatment goals and may guide the tapering of other therapies. Corticosteroids or IS therapy should be used in all patients with MG who have not met treatment goals after an adequate trial of pyridostigmine.
2. A nonsteroidal IS agent should be used alone when corticosteroids are contraindicated or refused. A nonsteroidal IS agent should be used initially in conjunction with corticosteroids when the risk of steroid side effects is high based on medical comorbidities. A nonsteroidal IS agent should be added to corticosteroids when:
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- a. Steroid side effects, deemed significant by the patient or the treating physician, develop;
- b. Response to an adequate trial (table e-1) of corticosteroids is inadequate; or
- c. The corticosteroid dose cannot be reduced due to symptom relapse.
3. Nonsteroidal IS agents that can be used in MG include azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, and tacrolimus. The following factors should be considered in selecting among these agents:
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- a. There is widespread variation in practice with respect to choice of IS agent since there is little literature comparing them
- Expert consensus and some RCT evidence support the use of azathioprine as a first-line IS agent in MG.
- c. Evidence from RCTs supports the use of cyclosporine in MG, but potentially serious adverse effects and drug interactions limit its use.
- d. Although available RCT evidence does not support the use of mycophenolate and tacrolimus in MG, both are widely used, and one or both are recommended in several national MG treatment guidelines.4,–,7
4. Patients with refractory MG should be referred to a physician or a center with expertise in the management of MG. In addition to the previously mentioned IS agents, the following therapies may also be used in refractory MG:
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- a. Chronic IVIg and chronic PLEX (see IVIg and PLEX, no. 6);
- b. Cyclophosphamide;
- c. Rituximab, for which evidence of efficacy is building, but for which formal consensus could not be reached.
5 IS agent dosage and duration of treatment
- a. Once patients achieve treatment goals, the corticosteroid dose should be gradually tapered. In many patients, continuing a low dose of corticosteroids long-term can help to maintain the treatment goal.
- b. For nonsteroidal IS agents, once treatment goals have been achieved and maintained for 6 months to 2 years, the IS dose should be tapered slowly to the minimal effective amount. Dosage adjustments should be made no more frequently than every 3–6 months (table e-1).
- c. Tapering of IS drugs is associated with the risk of relapse, which may necessitate upward adjustments in dose. The risk of relapse is higher in patients who are symptomatic, or after rapid taper.
- d. It is usually necessary to maintain some immunosuppression for many years, sometimes for life.
IVIg and PLEX.
- 1. PLEX and IVIg are appropriately used as short-term treatments in patients with MG with life-threatening signs such as respiratory insufficiency or dysphagia; in preparation for surgery in patients with significant bulbar dysfunction; when a rapid response to treatment is needed; when other treatments are insufficiently effective; and prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations.
- 2. The choice between PLEX and IVIg depends on individual patient factors (e.g., PLEX cannot be used in patients with sepsis and IVIg cannot be used in renal failure) and on the availability of each.
- 3. IVIg and PLEX are probably equally effective in the treatment of severe generalized MG.
- 4. The efficacy of IVIg is less certain in milder MG or in ocular MG.
- 5. PLEX may be more effective than IVIg in MuSK-MG.
- 6. The use of IVIg as maintenance therapy can be considered for patients with refractory MG or for those in whom IS agents are relatively contraindicated.
Thymectomy in MG.
- 1. In non-thymomatous MG, thymectomy is performed as an option to potentially avoid or minimize the dose or duration of immunotherapy, or if patients fail to respond to an initial trial of immunotherapy or have intolerable side effects from that therapy. Because of the long delay in onset of effect, thymectomy for MG is an elective procedure. It should be performed when the patient is stable and deemed safe to undergo a procedure where postoperative pain and mechanical factors can limit respiratory function.
2. The value of thymectomy in the treatment of prepubertal patients with MG is unclear, but thymectomy should be considered in children with generalized AChR antibody-positive MG:
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- a. If the response to pyridostigmine and IS therapy is unsatisfactory; or
- b. In order to avoid potential complications of IS therapy.
For children diagnosed with seronegative generalized MG, the possibility of a congenital myasthenic syndrome or other neuromuscular condition should be entertained, and evaluation at a center specializing in neuromuscular diseases is of value prior to thymectomy.
- 3. With rare exceptions, all patients with MG with thymoma should undergo surgery to remove the tumour. Removal of the thymoma is performed to rid the patient of the tumour and may not produce improvement in MG. All thymus tissue should be removed along with the tumour. Further treatment of thymoma will be dictated by histologic classification and degree of surgical excision. Incompletely resected thymomas should be managed after surgery with an interdisciplinary treatment approach (radiotherapy, chemotherapy).
- 4. In elderly or multimorbid patients with thymoma, palliative radiation therapy can be considered in the appropriate clinical setting. Small thymomas may be followed without treatment unless they are enlarging or become symptomatic.
- 5. Endoscopic and robotic approaches to thymectomy are increasingly performed and have a good track record for safety in experienced centers. Data from randomized, controlled comparison studies are not available. Based on comparisons across studies, less invasive thymectomy approaches appear to yield similar results to more aggressive approaches.
- 6. Thymectomy may be considered in patients with generalized MG without detectable AChR antibodies if they fail to respond adequately to IS therapy or to avoid/minimize intolerable adverse effects from IS therapy. Current evidence does not support an indication for thymectomy in patients with MuSK, LRP4, or agrin antibodies.
Juvenile MG (see also Thymectomy in MG, no. 2).
- 1. Children with acquired autoimmune ocular MG are more likely than adults to go into spontaneous remission. Thus, young children with only ocular symptoms of MG can be treated initially with pyridostigmine. Immunotherapy can be initiated if the goals of therapy are not met.
- 2. Children are at particular risk of steroid side effects, including growth failure, poor bone mineralization, and susceptibility to infection, due in part to a delay in live vaccinations. Long-term treatment with corticosteroids should use the lowest effective dose to minimize side effects.
- 3. Maintenance PLEX or IVIg are alternatives to IS drugs in JMG.
MG with MuSK antibodies.
- 1. Many patients with MuSK-MG respond poorly to ChEIs, and conventional pyridostigmine doses frequently induce side effects.
- 2. Patients with MuSK-MG appear to respond well to corticosteroids and to many steroid-sparing IS agents. They tend to remain dependent on prednisone despite concomitant treatment with steroid-sparing agents.
- 3. MuSK-MG responds well to PLEX, while IVIg seems to be less effective.
- 4. Rituximab should be considered as an early therapeutic option in patients with MuSK-MG who have an unsatisfactory response to initial immunotherapy.
MG in pregnancy.
- 1. Planning for pregnancy should be instituted well in advance to allow time for optimization of myasthenic clinical status and to minimize risks to the fetus.
- 2. Multidisciplinary communication among relevant specialists should occur throughout pregnancy, during delivery, and in the postpartum period.
- 3. Provided that their myasthenia is under good control before pregnancy, the majority of women can be reassured that they will remain stable throughout pregnancy. If worsening occurs, it may be more likely during the first few months after delivery.
- 4. Oral pyridostigmine is the first-line treatment during pregnancy. IV ChEIs may produce uterine contractions and should not be used during pregnancy.
- 5. Thymectomy should be postponed until after pregnancy as the benefit is unlikely to occur during pregnancy.
- 6. Chest CT without contrast can be performed safely during pregnancy, although the risks of radiation to the fetus need to be carefully considered. Unless there is a compelling indication, postponement of diagnostic CT until after delivery is preferable.
- 7. Prednisone is the IS agent of choice during pregnancy.
- 8. Current information indicates that azathioprine and cyclosporine are relatively safe in expectant mothers who are not satisfactorily controlled with or cannot tolerate corticosteroids. Current evidence indicates that mycophenolate mofetil and methotrexate increase the risk of teratogenicity and are contraindicated during pregnancy. (These agents previously carried Food and Drug Administration [FDA] Category C (cyclosporine), D (azathioprine and mycophenolate mofetil), and X (methotrexate) ratings. The FDA has recently discontinued this rating system, and replaced it with a summary of the risks of using a drug during pregnancy and breastfeeding, along with supporting data and “relevant information to help health care providers make prescribing and counselling decisions”12)
