Suite de la publication Lignes directrices pour un consensus international dans la gestion de la Myasthénie
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Consensus Guidelines for the Treatment of Myasthenia Gravis
Tori Rodriguez, MA, LPC
July 08, 2016
Myasthenia gravis (MG) is estimated to affect up to 60 000 Americans and over 700 000 people worldwide, though rates are likely even higher because the disease remains underdiagnosed. The prognosis for patients with MG has improved in recent years, due largely to the increasing use of immunomodulating therapies.
However, despite widespread agreement on the use of many MG treatments, there is still no universal standard of care to help guide clinicians. Because of the heterogeneous nature of the disease, no particular treatment approach is optimal for all patients with MG, and most physicians do not treat it often enough to be familiar with the full range of treatment options. Additionally, the “few successful clinical trials in MG have limited generalizability, and even the best of clinical trials cannot balance the use of different available and accepted treatment modalities in a disease as heterogeneous as MG,” explained Donald B. Sanders, MD, a professor of neurology at Duke University School of Medicine in Durham, North Carolina.
As a result of these factors, few “treatments used for MG have Class I evidence of efficacy, and it is increasingly difficult for physicians to get approval for the use of accepted therapies from payors,” he told Neurology Advisor. Some payors have even challenged the use of plasma exchange – which is universally accepted as an effective and critical component of MG treatment – because a major publication stated that there is insufficient evidence to support or refute its use for MG. Given this combination of circumstances, the “consensus process is specifically suited to provide guidance in such a situation,” Dr Sanders said.
To develop consensus-based MG treatment guidelines intended for clinicians worldwide, a task force appointed by the Myasthenia Gravis Foundation of America – of which Dr Sanders is a co-chair – selected a panel of 15 MG experts to “represent the breadth of knowledge and experience and a wide variety of opinions from MG experts internationally,” according to the paper. The experts first voted and agreed upon preliminary definitions of key concepts, including treatment goals, minimal manifestations, remission, ocular MG, impending and manifest crisis, and refractory MG. The panel then met to identify 7 treatment topics to address and to develop initial guidance statements.
After several rounds of anonymous email voting and modifications based on input from panel members, consensus guidelines were developed for the following areas: symptomatic and immunosuppressive treatment of MG, IV immunoglobulin and plasma exchange, treatment of impending and manifest myasthenic crisis, thymectomy in MG, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase (MuSK), and management of MG in pregnancy. Below are summary highlights from each area of the guidelines.
Symptomatic and IS Treatment of MG
- For most patients with MG, the intitial treatment should include pyridostigmine, and the dose should be adjusted as needed. If treatment goals have not been met after a trial of pyridostigmine, corticosteroids or IS therapy should be used.
- If corticosteroids cannot be used, a nonsteroidal IS agent should be used alone.
- A nonsteroidal IS agent should be used in conjunction with corticosteroids if significant side effects develop or there is a high risk of such based on comorbidities; the patient does not respond to an adequate trial of corticosteroids; or the dose of corticosteroids cannot be decreased because of symptom relapse.
- The nonsteroidal IS agents that can be used to treat MG include azathioprine, cyclosporine, mycophenolate mofetil, methotrexate, and tacrolimus. Since there is minimal data comparing these agents, there is significant practice variation in choosing among them. However, expert “consensus and some RCT evidence support the use of azathioprine as a first-line IS agent in MG,” and RCT findings support “the use of cyclosporine in MG, but potential serious adverse effects and drug interactions limit its use,” note the authors.
- Physicians should refer patients with refractory MG to a specialist or center with expertise in MG management. In addition to the IS agents mentioned above, chronic IVIg and chronic PLEX, cyclophosphamide, and rituximab can also be used in refractory MG.
Dosage and duration of treatment
- The dose of corticosteroids should be tapered after patients reach treatment goals, and a continued, long-term low dose can help maintain the treatment goal for some patients. “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,” said the authors, and adjustments should be made no more than every 3–6 months.
- Tapering of IS drugs is associated with risk of relapse, in which case increased doses may be required. This risk is higher after rapid taper or in symptomatic patients. It is typically necessary to maintain some IS therapy for many years or life.
- Patients on IS drugs must be monitored for adverse effects and other potential complications, and switching to another IS agent should be considered if these become significant.
IVIg and PLEX
- These are used as short-term treatments in the following situations: in MG patients who have life-threatening signs like respiratory insufficiency or dysphagia; in preparation for surgery in patients with significant bulbar dysfunction; when a rapid treatment response is needed; when other treatments are insufficient; and before starting corticosteroids if needed to prevent or minimize exacerbations.
- The availability of each therapy and individual patient factors determine the choice between PLEX and IVIg. For example, PLEX cannot be used in patients with sepsis, and IVIg cannot be used in those with renal failure.
- The two treatments are likely equally effective for severe generalized MG, though the “efficacy of IVIg is less certain in milder MG or in ocular MG,” and “PLEX may be more effective than IVIg in MuSKMG,” as stated in the guidelines. For patients with refractory MG or those who cannot take IS agents, IVIg as maintenance therapy can be considered.
Impending and manifest myasthenic crisis
- These are emergent situations requiring aggressive treatment. “PLEX and IVIg are the mainstay of management in myasthenic crisis,” according to the paper, and they are used as short-term treatment in these cases, while corticosteroids or other IS agents may be initiated concurrently for sustained clinical response. While research findings suggest that IVIg and PLEX are equally effective in treating impending or manifest myasthenic crisis, expert consensus suggests that PLEX is more effective.
- Impending crisis requires hospital admission and close observation of respiratory and bulbar function, with the ability to transfer to an intensive care unit if it progresses to manifest crisis,” and myasthenic crisis requires admission to an ICU or step-down unit for monitoring and management.
Thymectomy in MG
- Thymectomy is an elective procedure that may be performed with the aim of avoiding or minimizing immunotherapy, or if patients are non-responsive to it or have intolerable side effects.
- “With rare exceptions, all patients with MG with thymoma should undergo surgery to remove the tumor,” though this may not result in MG improvement, and additional “treatment of thymoma will be dictated by histologic classification and degree of surgical excision,” the guidelines state.
- Because children with acquired autoimmune ocular MG are more likely to go into spontaneous remission than adults, those with only ocular MG symptoms can be treated initially with pyridostigmine, and immunotherapy can be initiated if treatment goals are not met.
- Long-term steroid treatment should use the lowest effective dose, as children have an especially high risk of side effects from these drugs. “Maintenance PLEX or IVIg are alternatives to IS drugs in JMG,” the authors wrote.
MG with MuSK antibodies
MG in pregnancy
- “Many patients with MuSK-MG respond poorly to ChEIs, and conventional pyridostigmine doses frequently induce side effects,” according the the guidelines.
- These patients seem to respond well to corticosteroids and many steroid-sparing IS agents, though they “tend to remain dependent on prednisone despite concomitant treatment with steroid-sparing agents.”
- Patients with MuSK-MG tend to respond well to PLEX, and IVIg appears to be less effective. For those who have an insufficient response to initial immunotherapy, rituximab should be considered as an option.
Dr Sanders said that “physicians will probably find most helpful the statements on the use of steroids and secondary immunosuppressants, and the role of plasma exchange and IVIg.”
- Advance planning for pregnancy is ideal to allow sufficient time to optimize the patient's clinical status, and most women will remain stable throughout pregnancy if their MG is under control before pregnancy. “Multidisciplinary communication among relevant specialists should occur throughout pregnancy, during delivery, and in the postpartum period,” according to the paper.
- The first-line treatment for pregnant MG patients is oral pyridostigmine, and the IS agent of choice is prednisone.
- Thymectomy should wait until after pregnancy, as should chest CT unless there is a compelling indication otherwise.
- Evidence suggests that mycophenolate mofetil and methotrexate should not be used during pregnancy because of an increased risk of teratogenicity.
- Current information indicates that “azathioprine and cyclosporine are relatively safe in expectant mothers who are not satisfactorily controlled with or cannot tolerate corticosteroids,” though “there was a strong minority opinion against the use of azathioprine in pregnancy” based on a small number of case reports and animal studies.
- PLEX or IVIg are useful when a quick response is required during pregnancy, though maternal and fetal risks should be carefully considered.
- “All babies born to myasthenic mothers should be examined for evidence of transient myasthenic weakness, even if the mother's myasthenia is well-controlled, and should have rapid access to neonatal critical care support,” said the authors.
Though the panel acknowledges variation in practice patterns and treatment availability, Marinos C. Dalakas, MD, director of the Neuromuscular Disease Program at Thomas Jefferson University in Philadelphia, the author of an editorial piece regarding the document, stated that some of the information used to develop the guidelines is potentially out of date or is not accepted by other experts. Dr Dalakas believes the guidelines are helpful overall and commends the efforts of the panel. However, he wrote, “Several of the non-evidence based consensus opinions are not necessarily shared by other experts and some opinions need highlighting, while some old or untested views merit revisiting.”
For example, treatment goals were based on criteria defined by the 2000 Myasthenia Gravis Foundation of American Task Force, and he believes those criteria should be revised to consider more recent advances in immunotherapies. In addition, the panel's suggestion “that IVIg can be considered as maintenance therapy lacks support and may lead to overuse of this expensive drug,” Dr Dalakas said. Despite these and other points of disagreement, he acknowledges the value of the guidelines while concluding that consensus regarding treatment of MG remains incomplete.
The panel emphasized that the guidelines are not intended to be absolute treatment recommendations or to be used in the establishment of payment policies by payors. “New information about the treatment of MG that becomes available will trigger appropriate modifications to these guidance statements,” Dr Sanders said. “These guidance statements and the process used in developing them can serve as an example for developing guidance statements for other conditions for which there is no generally-accepted standard of care,” he said.
- Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis. Neurology. 2016; doi:10.212/WNL.0000000000002790.
- Dalakas MC. Treating myasthenia on consensus guide: Helpful and challenging but still unfinished business. Neurology. 2016; doi:10.1212/WNL.0000000000002796.