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Abstract

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder characterized primarily by fluctuating skeletal muscle weakness affecting ocular, bulbar, truncal, limb, and respiratory muscles. The disease is typically mediated by anti-acetylcholine receptor (AChR) antibodies, and less commonly by anti-muscle-specific kinase) or anti-low-density lipoprotein receptor-related protein 4 antibodies. Despite significant advancements in diagnostics and immunotherapy, disparities in treatment access and practice variability remain prevalent in Israel. To address these gaps, updated national guidelines have been developed, integrating the latest international evidence and adapting it to the local healthcare landscape, regulation, and population diversity. This national guideline emphasizes precise diagnostic evaluation through comprehensive clinical assessment, standardized antibody testing, neurophysiological studies, and mediastinal imaging for thymic pathology assessment. Utilizing standardized scales, including MG activities of daily living, quantitative MG score, and MG Foundation of America post-intervention status, is crucial for disease staging and therapeutic decision-making. Therapeutic goals prioritize achieving full remission or a state of minimal manifestations of disease with negligible treatment-related side effects. Guidelines for treatment strategies are based on antibody status, disease severity, patient age, and comorbidities. Thymectomy is recommended for patients with generalized AChR antibody-positive MG, ideally within 2 years of disease onset. Pregnant women, older adults, children, and patients with cancer need specific immunotherapy approaches. Multidisciplinary care, structured patient education, and psychosocial support are integral to managing MG effectively. These national guidelines aim to standardize clinical practices, enhance patient outcomes, and reduce healthcare disparities in the management of MG across Israel.

Plain language summary

National guidelines for management of myasthenia gravis in Israel

Myasthenia gravis (MG) is a chronic disease where the body’s immune system mistakenly attacks the proteins on muscles, eventually causing weakness effecing the eyes, face, arms, legs, and breathing. Occuring most often due to auto-antibodies against a molecule called the acetylcholine receptor (AChR). Although medical care for MG has improved a lot, people in Israel still face differences in how the disease is diagnosed and treated. Best of our county experts created updated national guidelines. These new guidelines combine the latest global research with the realities of healthcare in Israel. They recommend using clear steps for diagnosis, including physical exams, blood tests for antibodies, nerve tests, and chest imaging to look for problems with the thymus gland. Doctors are encouraged to use scoring systems, like the MG-ADL and QMGS, to track how patients are doing and guide treatment decisions. The main goal is to help patients reach full recovery or to have very few symptoms, with as few side effects from treatment as possible. Treatment plans are based on things like which antibodies a patient has, how severe the disease is, age, and other health conditions. Surgery to remove the thymus is suggested for certain patients, especially early in the disease. Special care plans are needed for pregnant women, children, older adults, and people with cancer. The guidelines also stress the importance of teamwork among different health specialists, teaching patients about their disease, and providing emotional support. Overall, these national guidelines are meant to ensure that all MG patients in Israel get better, more equal care.

Keywords

AChR antibodies autoimmune Israel LRP4 antibodies MuSK antibodies myasthenia gravis neuromuscular junction treatment guidelines

Introduction

Myasthenia gravis (MG) is the most common acquired disorder of neuromuscular transmission. It is characterized by the production of pathogenic autoantibodies directed against components of the neuromuscular junction, most frequently the acetylcholine receptor (AChR).¹ Muscle-specific kinase (MuSK)-positive MG often presents with a different clinical course and may require specific therapeutic strategies.² The estimated incidence of MG ranges from 0.3 to 2.8 cases per 100,000 population, with a global prevalence of approximately 700,000 individuals.³ It is, in fact, a chronic autoimmune disease of the neuromuscular junction characterized by fluctuating skeletal muscle weakness that commonly affects ocular, bulbar, limb, truncal, and respiratory muscles.⁴ MG is most commonly caused by autoantibodies targeting the postsynaptic AChR and less frequently by autoantibodies to MuSK and low-density lipoprotein receptor-related protein 4 (LRP4).⁵

Until the past two decades, most treatments for MG were evaluated primarily through retrospective clinical studies. More recently, however, several randomized controlled trials have been conducted. These advancements have been associated with significant improvements in both survival and overall prognosis for patients with MG.⁶ Yet, the absence of controlled trials that compare the efficacy of conservative and new treatments, their optimal combination or sequential use, and disparities in access to the new therapeutics results in considerable variation in treatment approach.

These guidelines aim to standardize MG diagnosis and provide a consistent roadmap to management decisions, aligning with national healthcare standards based on the latest best international practices recommendations, based on antibody status, disease activity, and medication records. We incorporated adaptations that are specific to Israel’s public health system, addressing medication availability. The limited availability of published Israeli epidemiological^7,8 data remains a challenge, strengthening the local evidence base for refining and tailoring guideline recommendations to better serve our patient population. This work represents a joint effort between the Neuroimmunology Society and the Neuromuscular Society.

Our goal is to provide a unified, practical guideline tailored to local treatment standards, serving as a comprehensive tool for neurologists across the region.

Methodology

Clinical criteria

A comprehensive clinical evaluation is the cornerstone of the diagnostic process for MG.⁴ This evaluation should focus on identifying the hallmark features of neuromuscular junction disorders, such as fluctuating muscle weakness and fatigability involving the ocular, bulbar, limb, truncal, and respiratory muscles. It is critical to exclude other potential causes of muscle weakness, including central nervous system pathologies (such as brain or spinal cord lesions), radiculopathies, myopathies, or peripheral neuropathies.

Antibody testing

All newly suspected cases should undergo testing for:

Anti-AChR antibodies (primary test)

Anti-MuSK antibodies, if anti-AChR negative

Anti-LRP4 antibodies, in selected double seronegative cases.

Anti-AChR antibody testing: The primary serologic investigation involves detecting antibodies against the acetylcholine receptor (anti-AChR). A positive test supports the diagnosis of the most generic form of MG. However, false-positive cases may be identified.⁴ Anti-MuSK Antibody testing: In patients with a negative anti-AChR test, testing for antibodies against MuSK should be performed^9,10 and if negative for LRP4.

Anti-LRP4 antibody testing: In selected cases of double seronegative MG (where both anti-AChR and anti-MuSK are negative), should be assessed.¹¹ This may be particularly useful when the diagnosis of MG remains unclear.^2,11 In rare cases, we reserve the physician’s decision to perform antibody screening to identify rare double-positive subtypes AChR/LRP4, AChR/MuSK presenting MG overlap syndromes. In a few cases, triple seronegative patients (negative for AChR, MuSK, and LRP4 antibodies) may resemble other neuromuscular disorders and should prompt consideration of other neuromuscular diseases such as oculopharyngeal muscular dystrophy (OPMD), chronic progressive external ophthalmoplegia (CPEO), Lambert–Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS). Electrophysiological studies are essential for diagnosis, alongside careful exclusion of these alternative conditions.¹²

Preferred assay methods: Radioimmunoassay (RIA) is a widely used and highly sensitive method for the detection of anti-AChR antibodies and remains a valuable tool in many diagnostic laboratories worldwide.¹³ However, due to limitations in local infrastructure and reagent availability, RIA is not routinely employed in clinical practice. Instead, cell-based assays (CBA) and enzyme-linked immunosorbent assays (ELISA) are more commonly utilized.¹⁴

Neurophysiological studies

Supportive diagnostic tools include repetitive nerve stimulation (RNS) and single fiber EMG (SFEMG), the latter being the most sensitive when performed on clinically involved muscle, but has lower specificity. Edrophonium (Tensilon) and ice pack testing should not be used as the primary diagnostic approach. Low-frequency RNS is a well-established diagnostic technique that assesses the decline in muscle action potential. A significant decremental response, defined as a reduction of more than 10% in compound muscle action potential amplitude, will be considered supportive of a diagnosis of myasthenia gravis. SFEMG is the most sensitive neurophysiological test for detecting impaired neuromuscular transmission.¹⁵ It measures the variability, or “jitter,” in the firing intervals between two muscle fibers innervated by the same motor neuron. Abnormal jitter is highly indicative of a transmission defect and, while not specific to MG, strongly supports the diagnosis in the appropriate clinical context.

Mediastinal chest imaging

Imaging of the mediastinum with either chest computed tomography (CT) or magnetic resonance imaging (MRI) is essential in all patients who test positive for anti-AChR antibodies, searching for thymoma.¹⁶ The primary goal of imaging is to evaluate the thymus gland for the presence of thymoma or thymic hyperplasia. Thymectomy is essential in the setting of thymoma.¹⁷

Standardized scales

Myasthenia Gravis Foundation of America (MGFA) clinical classification: this is the primary classification system that categorizes MG into different classes based on clinical severity—from ocular involvement only to severe generalized disease and myasthenic crisis.¹⁸ The MGFA post-intervention status (PIS) provides a framework for treatment goals. Myasthenia Gravis Activities of Daily Living (MG-ADL): this patient-reported scale assesses the impact of MG on daily activities such as chewing, speaking, and breathing.¹⁸ It is useful for both initial evaluation and ongoing monitoring of treatment response. Quantitative MG Score (QMG): a performance-based scale that quantitatively measures muscle strength and fatigability through a series of clinical tests.¹⁸ It provides a semi-objective measure of disease severity.

We additionally recommend the routine use of standardized, disease-specific instruments—specifically, the 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r)^19,20 and the Myasthenia Gravis Composite (MGC) alongside the above-established clinical scores. Given the high prevalence of psychological comorbidities in MG, validated tools for fatigue, depression, and anxiety can also be incorporated. These recommendations follow international-consortium guidance, which advocates standardized outcome measures and systematic screening of comorbid conditions in both phase III trials and routine clinical practice.

Clinical subtypes and classification

Patients should be classified by antibody status and clinical phenotype, as follows:

Ocular MG—restricted to eye muscles

Generalized MG

Early onset (<50 years)

Late-onset (⩾50 years)

Thymoma-associated (TAMG)

Anti-AChR antibody positive

Anti-MuSK antibody positive

Anti-LRP 4 antibody positive

Double/triple seronegative MG

It is recommended that neurologists use the MGFA clinical classification for staging and disease severity and outcome scoring systems such as MG-ADL, QMG, or any other similar method for longitudinal follow-up.

Results

Clinical approach and treatment principles

The primary therapeutic goal in managing MG is to achieve either complete stable remission off medication, pharmacological remission, or minimal manifestation status without inducing significant long-term adverse effects.²¹ Minimal manifestation status is defined as a clinical state in which the patient has no symptoms or functional limitations due to MG, although mild residual weakness in some muscle groups may still be present on careful examination. This definition acknowledges that some patients, while not meeting full remission criteria, may exhibit minimal residual deficits. The therapeutic objective also requires that any treatment-related adverse effects be no greater than grade 1 according to the Common Terminology Criteria for Adverse Events (CTCAE)²²; that is, asymptomatic or mildly symptomatic side effects that do not necessitate medical intervention.

Disease control in MG can be classified into three states: (1) complete disease control characterized by no detectable disease activity and either absence of residual symptoms or minimal, stable residual symptoms (incomplete remission), (2) incomplete disease control marked by ongoing disease activity, instability, deterioration, symptom fluctuation, and potentially new or worsening symptoms, with or without crises, and (3) no disease control, defined by high disease activity, persistent symptoms, potential crisis-like deteriorations, and resistance to therapeutic interventions. The second and third states include refractory MG.²³

The definition of high disease activity or treatment-refractory MG is commonly defined as generalized MG (MGFA clinical classification IIB or higher) that remains very active and inadequately responsive to pharmacological therapy (continuous symptoms with or without crises or crisis-like deteriorations, resistance to therapy).²⁴ This condition develops in approximately 8%–13% of patients²⁵ and encompasses several scenarios: (1) Inadequate improvement, uncontrolled symptoms, failure to achieve disease stability despite treatment with corticosteroids and at least one additional immunosuppressive agent, (2) inability to reduce corticosteroid dose equivalent to 10 mg prednisone or less, due to continued weakness or exacerbations requiring treatment with plasma exchange or intravenous immunoglobulins (IVIg), (3) recurrent exacerbations with imminent or actual myasthenic crisis, requiring courses of plasma exchange or IVIg, and (4) intolerable side effects from immunotherapies, and/or existence of comorbidities that present contra-indications to standard immunotherapies also place patients in this category. MG that is very active, resistant to treatment, or complicated by significant side effects and comorbidities represents a severe disease state requiring escalation in management that includes rapid-onset, high-efficacy medications.

Special populations

In addition to those with highly active disease, certain patient groups require individualized treatment strategies due to physiological differences, comorbid conditions, or an increased risk of treatment-related complications. Pregnancy necessitates a personalized therapeutic approach. Pyridostigmine, azathioprine, IVIG, plasma exchange, and corticosteroids are generally considered safe during pregnancy. However, medication use should be minimized to the lowest effective dosing, and teratogenic agents or those lacking safety data in pregnancy should be avoided whenever possible. Close collaboration with obstetric care providers is essential. Frail and older adults, particularly those over 65, often have increased susceptibility to the adverse effects of immunosuppressive therapies. This includes a heightened risk of infection, thromboembolic events, steroid-induced metabolic disturbances, malignancies, and bone loss. Treatment in this population should be guided by a comprehensive geriatric assessment, with particular attention to drug–drug interactions, cognitive status, frailty, and vascular risk. In early onset MG patients (ages 18–65), coexisting autoimmune disorders such as systemic lupus erythematosus, inflammatory bowel disease, and autoimmune thyroid disease are common and mandate an interdisciplinary approach to immunotherapy selection. Children and adolescents with MG require special consideration related to growth, puberty, and long-term developmental outcomes. Corticosteroids and immunosuppressants may interfere with growth velocity and bone development; thus, treatment plans should emphasize early disease control using the minimal effective dose and duration. Psychosocial and educational support should also be integrated into care.

Patients with active or prior malignancy present additional complexity in the management of MG. By itself, chronic use of immunosuppressive agents such as azathioprine,²⁶ mycophenolate mofetil,²⁷ and rituximab²⁸ has been associated with varying degrees of cancer risk, depending on the drug, duration of therapy, and patient population. They may carry theoretical or documented risks of tumor progression, recurrence, or impaired cancer surveillance. For patients undergoing active cancer treatment, coordination with oncology is critical to optimize exposure to immunosuppressive therapy and avoid adverse interactions. In cases where immunotherapy is contraindicated or must be limited, alternative approaches such as IVIG or plasma exchange may be prioritized. The choice of immunosuppressive agent should consider the type of malignancy, treatment phase, and overall prognosis.

General recommendations

Surgical therapy: Thymectomy, even in the absence of a thymoma, has been shown to improve long-term clinical outcomes in a randomized, rater-blinded study that enrolled patients aged 18–65 years with generalized AChR antibody-positive MG.²⁹ The procedure is especially beneficial when performed within the first 2 years of disease onset and between the ages of 18 and 50 years, and should be considered early during treatment in this subpopulation.²⁹ Of note that MuSK-Ab-positive generalized MG patients should not undergo thymectomy.

Pharmacological therapy: Chronic generalized MG associated with functional impairment requires immunosuppressive or immunomodulatory treatment. The choice of therapy should be guided by disease severity, antibody status, and the treating physician’s clinical judgment. Therapeutic options and principles for long-term management are outlined in the following sections. Symptomatic treatment with AchE inhibitors should be used as needed.

Patients with MG should receive structured education regarding lifestyle modifications that support disease management. This includes guidance on maintaining regular physical activity within individual tolerance levels and adopting stress-reduction techniques.

Medications with known associations to MG exacerbation are categorized according to the MGFA “cautionary drugs” framework, as outlined in the 2016 International Consensus Guidance for Management of Myasthenia Gravis (Sanders et al. 2016) Agents with strong evidence of precipitating myasthenic worsening—such as fluoroquinolones, telithromycin and botulinum toxin—are designated “avoid,” whereas drugs with lower or more variable risk—such as beta-blockers and statins—are classified as “use with caution” For each prescribed agent, we recommend a formal risk–benefit assessment that weighs the severity of the comorbid condition against the potential for MG exacerbation, comprehensive patient counseling to convey specific neuromuscular risks and early warning signs, and tailored clinical monitoring—such as baseline strength measurements and prompt follow-up during dose initiation or titration—to ensure rapid detection and management of any decline in muscle function.

Referral to a neurologist with expertise in neuroimmunology and neuromuscular disorders is strongly recommended for all patients, particularly those with moderate to severe disease or atypical presentations. Multidisciplinary collaboration, when available, should include physiotherapy, occupational therapy, speech and swallowing specialists, and psychosocial support services.

MG often leads to functional disability, which may be invisible to others and is frequently under-recognized by both healthcare systems and society. This also includes cognitive fatigue, social isolation, and difficulties with employment or education. It is essential to address coexisting anxiety, depression, and adjustment disorders, and to ensure that patients are informed of their legal rights and entitlements related to disability status and social support.

Treatment algorithm

First-Line Therapy (Table 1).

Table 1.

Treatment recommendations by clinical type, severity, and antibody status.

Clinical type	Disease severity	Abs	First-line Rx	Second-line Rx	Additional options
Ocular	Mild/Moderate	Any	Pyridostigmine	Glucocorticoids ± azathioprine, mycophenolate mofetil, methotrexate	Surgery-oculoplastic surgery
Generalized	Mild/Moderate	AChR-Ab positive	Glucocorticoids ± azathioprine; thymectomy	Glucocorticoids ± mycophenolate mofetil, methotrexate, Rituximab, tacrolimus	±Additional glucocorticoids, PE, IVIg
	Mild/Moderate	MuSK-Ab positive	Glucocorticoids ± azathioprine	Glucocorticoids ± Rituximab	PE, IVIg
	Highly active or Refractory	AChR-Ab positive	Complement inhibitors; FcRn modulators; thymectomy	Complement inhibitors/FcRn modulators ± immune suppressants/Rituximab	±Additional glucocorticoids, cyclophosphamide
	Highly active or Refractory	MuSK-Ab positive	Rituximab	FcRn modulators plasmapheresis; cyclophosphamide	±Additional glucocorticoids
Crisis	—	Any	IVIg; plasmapheresis; Glucocorticoids therapy	FcRn modulators, complement inhibitors

Patients are considered for advanced therapies if they have.

(a) ⩾MGFA IIb or ⩾2 severe exacerbations within 1 year despite adequate trials of conventional treatment and /or inability to reduce corticosteroids.

(b) Persistent daily living symptoms (⩾MGFA IIa) plus ⩾2 crisis in 12 months; or.

MGFA reflects current severity, not historical peak. Double seronegative and LRP4-positive MG are treated like AChR-Ab-positive MG. The efficacy of newer biologic therapies in these subgroups has not been established through dedicated clinical trials. Treatment decisions in such cases should therefore rely on clinical judgment and expert consensus until more specific evidence becomes available. Early steroid-sparing strategies are preferred. Some therapies listed may be off-label or reimbursement-dependent.

AChR, acetylcholine receptor; IVIg, intravenous immunoglobulin; LRP4, lipoprotein receptor-related protein 4; MG, Myasthenia gravis; MGFA, MG Foundation of America; MuSK, Muscle-specific kinase; PE, plasma exchange.

All patients: Pyridostigmine for symptomatic relief.³⁰

Generalized or ocular AChR\LRP4 antibody-positive MG

Corticosteroids serve as a pivotal immunosuppressive therapy and are often employed as the initial treatment in managing MG. If corticosteroids are not suitable or risky, consider alternative treatments.³¹ The initiation of corticosteroid therapy should be gradual to mitigate the risk of exacerbating muscle weakness, which could potentially lead to a myasthenic crisis. Conversely, during acute myasthenic exacerbation, particularly in intubated patients, commencing treatment with higher doses (approximately 1 mg/kg prednisone equivalent) may expedite clinical improvement after removing or neutralizing anti-AChR antibodies with plasmapheresis or IV immunoglobulin.

While corticosteroids are effective, often yielding noticeable improvement within several weeks, their long-term use is associated with significant adverse effects. Chronic corticosteroid therapy can lead to complications such as diabetes mellitus, hypertension, osteoporosis, gastrointestinal issues, vascular disease, and behavioral and sleep changes, all of which contribute to considerable morbidity and may reduce life expectancy. Given these potential complications, long-term corticosteroid use is generally discouraged. A primary goal of immunological management in MG is to minimize chronic corticosteroid exposure, including in patients that achieved remission, by transition to steroid-sparing agents. It is important to note that a favorable response to corticosteroids does not justify withholding other steroid-sparing therapies.³² In principle, corticosteroid dose should be reduced to below 10 mg prednisone equivalent per day, with an optimal daily dose of 5–7.5 mg per day.^33
–35

In most instances, initiating treatment with additional immunosuppressive or steroid-sparing agents is necessary. Since these agents typically have a slower onset of action, often requiring several months to achieve full efficacy, adjunctive therapies such as plasmapheresis or IVIg may be utilized concurrently to manage acute exacerbation or to bridge the period until immune suppression takes effect. These interventions can provide rapid symptomatic relief while awaiting the therapeutic effects of the primary disease-modifying immunosuppressive agents.

Steroid-sparing agents initiated early

Steroid-sparing immunosuppressive medications

The following agents can be considered as first to fourth line of treatment: azathioprine, mycophenolate, methotrexate, rituximab, and intravenous immunoglobulins (Table 1).

Azathioprine: Gradual dose escalation is recommended, increasing by 25–50 mg every 7–10 days with regular monitoring of complete blood count (CBC) and liver function tests (LFTs). The target dose is determined primarily by clinical response and can be monitored by reducing the white blood cell (WBC) count to a range of 4000–5000 cells/mm³ and/or lymphocyte count to 800–1200 cells/mm³, and/or an increase in MCV.

Mycophenolate, Cyclosporine, and Methotrexate: These medications are commonly used as alternatives when azathioprine causes side effects or complications. Methotrexate is typically administered once (and up to twice) weekly, followed by 5 mg of folic acid on the day after treatment.

Rituximab or Biosimilar: Rituximab, an anti-CD20 antibody, is particularly effective for MuSK antibody-positive MG.³⁶ Studies showed mixed results regarding efficacy in anti-AChR antibody-positive MG; however, some patients respond exceptionally well, particularly with early intervention. Rituximab may be used as an early line treatment when a faster (weeks to 3 months) therapeutic effect is required,³⁷ as other immunosuppressive agents like azathioprine typically take more months to reach efficacy. Novel anti-B cell therapies, such as anti-CD19 antibodies, may also add to the arsenal of therapies for MG.³⁸

Intravenous immunoglobulins: Short-term IVIg therapy has proven effective in myasthenic crises and disease exacerbations.³⁹ However, longer-term IVIg efficacy for improving outcomes or reducing corticosteroid requirements has not been demonstrated in placebo-controlled trials. Despite this, long-term IVIg treatment is widely accepted in many centers, is recommended in existing guidelines, and serves as a commonly utilized therapy with demonstrated steroid-sparing benefits (based on our research), often bridging the period until immunosuppressive agents, such as azathioprine, take effect.⁴⁰ IVIg is particularly recommended for pregnant women, growing children, or patients for whom steroids and other immunosuppressive medications are contraindicated or insufficiently effective.

FcRn antagonists interfere with the recycling mechanism of IgG occurring in endothelial cells lining blood vessels. These antagonists preferentially bind FcRn, leading to the lysosomal degradation rather than recycling of IgG antibodies, including pathogenic antibodies such as those against the AChR. Several FcRn inhibitors have demonstrated efficacy through phase III clinical trials. These include efgartigimod, rozanolixizumab, and nipocalimab, all of which have received international regulatory approvals. Batoclimab is another FcRn-targeting monoclonal antibody currently being evaluated in late-stage clinical development.⁴¹ Treatment can be administered intravenously or subcutaneously, repeated monthly as clinically necessary, or continued biweekly depending on the agent, the manufacturer’s labels, and the administration method. Clinical trials demonstrated significant improvement in patients with generalized MG (MGFA grade 2–4) with severe disease (MG-ADL ⩾5 or 6) who were already on standard therapy. Real-world experience has shown significant reductions in hospitalizations among MG patients. Few FcRN have already been approved in Israel, such as Efgartigimod in 2023 and Nipocalimab in 2025, both as a fifth-line therapy option for AChR antibody-positive MG, and may serve as an advanced therapeutic line also for anti-MuSK MG.⁴²

Complement inhibitors targeting complement proteins are also novel, highly effective drugs. They are associated with an increase in the risk of meningococcal infection by 1000 to 2000-fold, because of their mechanism of action inhibiting membrane attack complex (MAC) formation, which plays a key role in fighting off encapsulated bacterial infection.⁴³ Consequently, use of these agents requires prior vaccination against Neisseria meningitidis or prophylactic antibiotic treatment. Eculizumab, a humanized monoclonal antibody that binds complement protein C5, offers robust efficacy in patients with AChR antibody-positive MG by blocking C5 cleavage into C5a and C5b and preventing assembly of the MAC, which drives postsynaptic membrane injury. Ravulizumab, a newer generation with similar mechanisms, is also a human monoclonal antibody that binds C5 with higher affinity and sustains therapeutic blood levels for 8 weeks versus 2 weeks in Eculizumab, reducing dosing frequency. Its mechanism of action is based on neutralizing the terminal complement system by preventing C5a and C5b formation and the subsequent formation of the MAC. MAC-mediated postsynaptic membrane damage is well documented in AChR antibody-positive MG.⁴⁴ Ravulizumab was evaluated in a controlled clinical trial and demonstrated sustained improvement in patients with generalized AChR antibody-positive (MGFA grade 2–4) who had MG-ADL ⩾ 6. It may offer an additional treatment option for patients who have had an insufficient response to existing therapies. It was approved in Israel’s healthcare benefits package in 2023 as a fifth-line therapy.

Cyclophosphamide is reserved for special and rare cases, with one study showing substantial clinical improvement, allowing many patients to reduce or discontinue corticosteroids and injectable therapies. It was generally well-tolerated, with minimal adverse effects. The study supports its use for achieving rapid remission, reducing steroid dependence, and minimizing the need for ongoing intensive therapies in patients with acetylcholine receptor antibodies.⁴⁵ However, cyclophosphamide carries a high risk of long-term complications such as malignancy and cardiomyopathy, and its role will likely shrink further as targeted B- and T-cell therapies transform MG management

Treatment principles tailored to the current regulatory environment in Israel for myasthenia gravis

Early initiation of effective therapy. While the NMJ does exhibit plasticity, clinical experience and observational studies suggest that delayed treatment in MG may lead to persistent muscle weakness and suboptimal recovery, likely due to a combination of sustained immune-mediated injury and secondary structural or functional muscle changes. Therefore, we emphasize that early initiation of effective therapy is important to optimize outcomes, particularly when adequate control is not achieved with initial conventional treatment within the first year of diagnosis. Accordingly, it is essential to initiate high-efficacy therapy within 1 year of diagnosis if adequate response has not been achieved with appropriate use of conventional therapies.

Despite the advantages of early intervention, high-efficacy biologic therapies have also demonstrated significant benefit in patients with chronic disease. Therefore, prolonged disease duration should not be considered a contraindication to initiating such treatments.

Plasma exchange (plasmapheresis) is an established alternative to IVIg for both acute exacerbations and maintenance therapy. It is reasonable to attempt a transition to IVIg maintenance following a period of maintenance plasmapheresis. However, there is no obligation to try IVIg in patients who have received plasmapheresis before initiating biologic therapy.

Escalation to biologic therapies: Escalation to biologic therapies should be considered in patients who demonstrate persistently active disease despite an adequate trial of conventional treatments, typically over a period of approximately 3 months. This timeframe serves as a pragmatic clinical benchmark to reassess treatment effectiveness, particularly when corticosteroid tapering below 20 mg per day has not been feasible or sustained disease control has not been achieved. While we acknowledge that some immunosuppressants, such as azathioprine, have a delayed onset of action, the decision to escalate should be based on overall clinical trajectory, treatment tolerability, and disease burden. Escalation is particularly warranted in patients who have received corticosteroids in combination with a single conventional immunosuppressant and one additional modality such as rituximab, IVIg, or plasmapheresis. Current evidence supports the comparable efficacy of biologic agents targeting the neonatal Fc and the complement pathway (C5 inhibitors), and treatment choice should be guided by patient-specific factors, including antibody status, comorbidities, and access to therapies.

Initiation of high-efficacy biologic therapy is appropriate in patients with MG who have required at least two hospitalizations in the past year due to crises necessitating mechanical ventilation or GI tube insertion, even if all prior treatment lines have not been exhausted. In this category, we include the FcRN inhibitors and the oral or intravenous complement inhibitors.

Combination therapy with advanced biologics and conventional immunosuppressants is entirely appropriate. This was a common feature in the clinical trials leading to targeted therapy approvals and may be beneficial in selected cases. Moreover, in highly active MG, there is a biologic rationale to combine disease-modifying therapies, such as standard immunotherapies or Rituximab, with advanced biologics that are highly effective in controlling symptoms, but do not act as disease-modifying therapies.

Patients with double seronegative or LRP4-positive MG are generally managed according to the same treatment framework as those with AChR antibody-positive disease. For individuals with mild to moderate generalized symptoms, first-line therapy typically includes glucocorticoids with or without azathioprine, and thymectomy may be considered when appropriate. If clinical response is insufficient or limited by adverse effects, second-line immunosuppressive agents such as mycophenolate mofetil, methotrexate, rituximab, or tacrolimus may be employed. In cases of highly active or treatment-refractory disease, escalation to advanced immunotherapies, including complement inhibitors and FcRn modulators, may be considered, alone or in combination with other agents such as rituximab. Thymectomy remains an option in selected cases. It is important to note that the efficacy of newer biologic therapies in LRP4-positive and double seronegative subgroups has not been established through dedicated clinical trials. Therefore, treatment decisions in these populations should rely on clinical judgment and expert consensus until more targeted evidence becomes available.

Discussion

The strength of neuromuscular medicine guidelines relies on collaboration and expertise. Our nationally agreed-upon guidelines, developed with Israeli MG experts, combine scientific evidence and clinical experience tailored to Israel’s healthcare needs. Similar to international standards, our guidelines emphasize meticulous diagnostic assessment through antibody testing, neurophysiological studies, and mediastinal imaging. Comparable to the German,³¹ American,²¹ and Japanese³⁴ guidelines, antibody testing for AChR, MuSK, and LRP4 plays a central role in guiding diagnostic clarity and subsequent management decisions.

In therapeutic strategy, our guidelines advocate for individualized treatment decisions based on antibody status, disease severity, patient age, and comorbid conditions. This approach parallels international guidelines, but with subtle differences reflecting local healthcare considerations. Notably, our recommendation for thymectomy in generalized AChR-positive MG within 2 years of disease onset closely aligns with American and German recommendations informed by robust evidence from trials such as the MGTX. In line with global trends, our guidelines introduce clear definitions of disease activity and treatment-refractory MG, directly informing the decision-making process for initiating advanced immunotherapies, a practice mirrored particularly in the German guidelines, which explicitly categorize disease activity into defined clinical stages.

Special populations, including pediatric, late-onset, pregnancy-associated MG, and patients with coexisting autoimmune diseases, receive focused attention in our guidelines, consistent with the emphasis observed internationally. American guidelines further highlight specific management recommendations for MG associated with novel oncology treatments, which expands our perspective on special patient groups requiring distinct considerations. Furthermore, the Japanese guidelines notably classify MG into six distinct clinical subtypes to streamline targeted treatments, a concept we partially incorporate through antibody-based and clinical phenotype classification systems.

While the introduction of targeted biologic therapies such as complement inhibitors and FcRn antagonists marks a significant advancement in the treatment of generalized MG, their high cost remains a major consideration in clinical decision-making. Current evidence supporting their efficacy must be balanced against real-world constraints, particularly within a publicly funded healthcare system such as Israel. As long-term, head-to-head cost-effectiveness analyses are still emerging, it is essential that the use of these agents be reserved for patients with clearly defined refractory disease or those who have failed conventional immunotherapies, ensuring responsible resource allocation while maximizing clinical benefit.

Despite the comprehensive and collaborative nature of this guideline development process, several limitations should be acknowledged. First, the evidence base remains heavily weighted toward AChR antibody-positive MG, with limited high-quality data available for MuSK, LRP4, and triple seronegative subtypes. Second, while expert consensus and international alignment guided many recommendations, the lack of robust, population-specific epidemiological and clinical data from Israel constrains the extent to which certain recommendations can be tailored. Finally, the long-term efficacy and cost-effectiveness of emerging biologic therapies remain to be fully established, underscoring the need for ongoing evaluation and adaptation of these guidelines as new evidence and local data emerge.

Our guideline development combines expert consensus and evidence-based principles tailored to local needs, following international standards. Similar to German, American, and Japanese methodologies, our approach integrates current clinical trial data, expert opinion, and practical considerations specific to Israel’s healthcare landscape. Collectively, these parallels and nuanced differences highlight a global shift toward personalized, evidence-driven, and clinically relevant management strategies in MG care, ensuring comprehensive, effective patient management across diverse clinical contexts.

Conclusion

As therapeutic options for MG continue to evolve with several phase II and III trials of novel approaches underway, the Israeli guideline introduces disease activity as a core criterion for initiating advanced immunomodulatory therapies. This marks a shift toward a more adaptive and personalized approach to care.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Shahar Shelly

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National guidelines for diagnosis,treatment,and management of myasthenia gravis in Israel

Abstract

Plain language summary

Keywords

Introduction

Methodology

Clinical criteria

Antibody testing

Neurophysiological studies

Mediastinal chest imaging

Standardized scales

Clinical subtypes and classification

Results

Clinical approach and treatment principles

Special populations

General recommendations

Treatment algorithm

Generalized or ocular AChR\LRP4 antibody-positive MG

Steroid-sparing agents initiated early

Steroid-sparing immunosuppressive medications

Treatment principles tailored to the current regulatory environment in Israel for myasthenia gravis

Discussion

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References