Minimal Symptom Expression in Generalized Myasthenia Gravis: A Valuable Patient-Centric Treatment Goal.

1
Introduction
Generalized myasthenia gravis (MG) is a rare autoimmune disease characterized by antibody‐driven damage to the neuromuscular junctions (NMJ), resulting in symptoms ranging from fluctuating activity‐dependent weakness to life‐threatening respiratory failure [1, 2, 3]. Given the absence of a cure for gMG, treatment focuses on symptom management through reduction of disease activity. Although conventional therapies such as acetylcholinesterase inhibitors, corticosteroids, and nonsteroidal immunosuppressants remain widely used, many patients experience persistent symptoms, treatment‐limiting adverse events, or difficulty achieving desired disease control [4, 5].
The recent introduction of novel biologic therapies, such as complement inhibitors, B‐cell depleters, and FcRn blockers, has broadened the therapeutic landscape and created opportunities for more precise and patient‐centered approaches to defining treatment success [6, 7, 8, 9]. These biologics offer renewed optimism for achieving profound and sustained symptom control, potentially with a reduced burden of side effects compared to traditional therapies [6, 8]. As a result, biologics are increasingly considered earlier in the disease course, particularly for patients with high disease activity, inadequate response, or intolerance to corticosteroids and conventional immunosuppressants [6, 8, 10, 11].
Effective gMG disease assessment relies on a combination of clinician‐ and patient‐reported outcomes, allowing treatment to be tailored to individual needs and the variable course of the condition. In international consensus guidelines, the principal therapeutic aim has been the achievement of minimal manifestations (MM) or better, based on the Myasthenia Gravis Foundation of America Post‐Intervention Status (MGFA‐PIS) [5]. Under this framework, MM is defined as the absence of functional MG symptoms, although mild muscle weakness may still be observed upon examination. Consensus holds that MGFA‐PIS‐defined MM should reflect the overall clinical judgment of the provider rather than standardized thresholds or specific changes in outcome measure scores [12, 13]. However, the use of MM in both clinical practice and research has been limited by several challenges, including the absence of a standardized method of assessment, reliance on clinician judgment, and the lack of specified instruments to quantify MM. Subclassification of MM (MM‐0 to MM‐3) is increasingly considered of limited clinical value [12], and the duration requirement originally included in MGFA‐PIS definitions is inconsistently applied in modern clinical trials.
A major challenge for the MM definition is its subjectivity, as the relevant guidelines do not specify which instruments or criteria (e.g., clinical examination, functional outcome measures) should be used to measure MM. Consequently, the absence of specific instruments, as well as the clinical heterogeneity of gMG symptoms they are meant to capture, limits the utility of MGFA‐PIS‐defined MM in routine clinical practice and underscores the need for tools that accommodate diverse clinical profiles.
Some national guidelines have introduced operational refinements to make the treatment goals more actionable and patient‐centric. For example, the Japanese guidelines aim for “MM‐5 mg” (MM on ≤ 5 mg/day of prednisolone) [14], a state associated with enhanced quality of life (QoL) [14, 15, 16]. The guideline strongly emphasizes attaining this state as rapidly as possible, noting that the rate of patients achieving this goal plateaus after 5 years [14]. The German Neurological Society guideline promotes a broader treatment goal: achieving optimal disease control while restoring or preserving patient QoL [17]. To assess disease activity and severity, the German guideline mentions the use of Quantitative Myasthenia Gravis Score (QMG), the Myasthenia Gravis Activities of Daily Living (MG‐ADL), the MG‐Quality of Life 15 (MG‐QoL15r), and the current MGFA status (i.e., the assessment of severity at the time of clinical assessment). However, it does not clearly specify how full disease control should be defined, nor which instruments or criteria should be employed [18]. These limitations have prompted greater interest in outcome measures that are both clinically meaningful and practical for routine use.

2
Overview of gMG Assessment Tools
Several instruments are available to support clinicians and patients in evaluating gMG symptoms and their impact (Table 1). The QMG is a clinician‐administered scale focused on objectively measuring muscle strength and fatigability [19, 20]. The Myasthenia Gravis Composite (MGC) scale is a hybrid instrument; while it is completed by a clinician, it uniquely integrates objective examination findings with several subjective, patient‐reported items on functional impairment [21, 22]. The MG‐ADL [23, 24] MG‐QoL15 [26, 27] scales provide valuable insights into the disease's impact from the patient's perspective. The MG‐QoL15 has now been updated to the MG‐QoL15‐revised (MG‐QoL15r), which is now considered the standard owing to its improved psychometric properties [28] As many foundational studies were conducted with the original MG‐QoL15, familiarity with both versions is essential when reviewing the literature.
In addition to multi‐item scales, simple measures with one single direct question like the Patient Acceptable Symptom State (PASS) and the Single Simple Question (SSQ) are used to assess patient satisfaction [29]. The PASS asks if patients are satisfied with their current status (Yes/No), while the SSQ asks what percentage of normal they feel (0%–100%).
Among these tools, the MG‐ADL scale has become a widely adopted patient‐reported tool for quantifying symptom burden in clinical trials, real‐world studies, and treatment authorization pathways [30]. A recent European consensus on improving and standardizing disease assessment in gMG recommended the consistent use of MG‐ADL to measure disease activity in routine clinical practice, supplemented by a simple measure of patient satisfaction such as the PASS [30, 31]. Prior research has established the PASS thresholds corresponding to acceptable symptom states as ≤ 2, 7, and 8 for the MG‐ADL, QMG, and MG‐QoL15, respectively [32]. Building on this foundation, Minimal Symptom Expression (MSE), defined as an MG‐ADL score of 0 or 1, has emerged as a simple, interpretable, and patient‐centric indicator of minimal disease burden. Anchored to a standardized and validated instrument, MSE offers a more consistent, operationalizable target than traditional MM and may help address gaps in how treatment goals are defined, assessed, and communicated.
In this position paper, we review the rationale for MSE as a treatment goal, summarize supporting evidence from clinical trials and observational studies, and outline considerations for integrating MSE with clinician‐assessed and safety‐focused measures to support a comprehensive framework for individualized gMG management.

3
The MG‐ADL Rapidly and Reliably Captures the Impact of gMG From the Patient Perspective
The MG‐ADL assesses eight common symptoms: talking, chewing, swallowing, breathing, brushing teeth/combing hair, rising from a chair, double vision, and eyelid droop [23, 24]. Each item is linearly scored from 0 (normal) to 3 (severe), resulting in a total score ranging from 0 to 24. Its simplicity, rapid administration (typically < 10 min), and applicability across languages make it a practical tool for diverse clinical settings [33, 34, 35, 36]. As a patient‐reported outcome aligned with US Food and Drug Administration guidance on incorporating patient perspectives into drug development, the MG‐ADL captures daily functional impairments that are important to individuals with gMG [37].
Clinically, the MG‐ADL demonstrates strong psychometric performance, including high test–retest reliability and notable concordance between patient‐ and physician‐reported scores [25, 33, 34, 35, 36, 38]. It has been observed that patient symptoms as reflected by the ADL score may improve prior to clinician assessed scales, with increasing correlation over time [39, 40]. Further, the MG‐ADL is highly sensitive to clinical improvement, with an effect size of 1.22. In patients with mild‐to‐moderate MG, a 2‐point decline best predicted clinical improvement, defined as concordant improvement in physician's impression of change and in MG‐QoL15 scores [38]. Thus, an MG‐ADL improvement of 2 or 3 has been historically used to indicate meaningful clinical improvement.
In the past decade, the MG‐ADL has been increasingly recognized as a reliable endpoint in clinical research, and the FDA recommends its use as a patient‐reported clinical outcome assessment for clinical trials in gMG [41]. Consequently, the MG‐ADL has been widely adopted in recent pivotal trials of gMG treatments. A 2022 review found that 74% of phase 2/3 studies used the MG‐ADL as a secondary outcome and that the remainder used it as a primary outcome [30]. In observational MG studies, it served as the primary outcome in 82% of cases [30]. A multinational survey of clinicians similarly identified the MG‐ADL as the most commonly used instrument in routine practice [12]. In the US, payers also frequently require MG‐ADL scores to support MG treatment initiation and maintenance [42, 43, 44]. This growing endorsement underscores the utility of the MG‐ADL and its derived measures in defining treatment success and setting actionable therapeutic goals.
3.1
MSE Is an Achievable, Valuable, and Patient‐Centric Goal for Patients With gMG
MG‐ADL data can be analyzed in several ways, including assessing changes in total score from baseline and applying a responder threshold to indicate clinical improvement. More recently, MSE, defined as an MG‐ADL score of 0 or 1, indicating no or minimal interference from MG symptoms in activities of daily life, has gained attention as it provides a crucial patient perspective beyond physician assessments or laboratory markers [45]. MSE's reliance on the MG‐ADL also introduces inherent limitations as the measure cannot capture aspects of disease that fall outside the scale's scope, and some patients may still experience meaningful symptoms despite a low total score. Despite this important caveat, utilizing an absolute score to define minimal symptoms offers a more consistent measure than relative changes from baseline, which may mask residual disease burden in patients starting with high MG‐ADL scores.
By offering a straightforward definition of near‐absent symptoms, MSE has strong potential to standardize how minimal symptom or MM states are conceptualized in gMG. Its feasibility as a treatment target has increased with the introduction of new biologics, which have enabled a substantial proportion of patients, including those inadequately controlled on conventional therapies, to achieve MSE in clinical trials and real‐world practice [46, 47, 48, 49, 50, 51].

4
Achievement of MSE Across Phase III Randomized Trials (RCTs) of Approved Biologic Therapies for gMG
A targeted literature review was conducted by the authors in January 2025 and refreshed in June 2025, which identified eight phase III clinical trials of US‐approved biologics for gMG. These include three trials evaluating efgartigimod (ADAPT [52], ADAPT‐SC [53], ADAPT‐NXT [54, 55]) and one trial each evaluating eculizumab (REGAIN [56]), rozanolixizumab (MycarinG [57]), zilucoplan (RAISE [58]), ravulizumab (CHAMPION‐MG [59]), and nipocalimab (VIVACITY‐MG3 [60]). These studies enrolled patients with gMG with longstanding disease, many of whom had received multiple treatments prior to study participation. An overview of the design and MG‐ADL assessments used in these studies is presented in Table 2. MG‐ADL was the primary measure outcome in all the trials except ADAPT‐SC, where it was considered a secondary outcome.
During the RCT periods, a clear and consistent separation was observed between active treatment and placebo. MSE rates in the placebo arms were modest, ranging from 1.7% to 13.2%, while all active therapies demonstrated substantially higher rates (Figure 1A). In the subsequent open label extension (OLE) phases, reported MSE rates (ranging from 25.4% to 54.6%) for patients receiving active treatment were generally comparable to or higher than those seen in the active arms of the preceding RCTs (Figure 1B).
However, the reporting of MSE varied across trials, with some providing the proportion of patients who achieved MSE at any time during the study and others reporting rates at predefined time points (Table 2). The lack of a standardized analytical approach and differences in study populations hinder the ability to effectively compare trial outcomes. Notwithstanding this limitation, our findings support MSE as a clinically relevant and achievable treatment goal in the management of gMG, including among patients with suboptimal response to conventional therapies. While newer biologics show promise, treatment should remain individualized and guided by disease severity, comorbidities, prior treatment response, and patient preferences. As such, MSE remains a meaningful, patient‐centered treatment goal that can help guide decision‐making in modern gMG care.
While this position paper focuses on approved biologics in RCTs, it is important to note that treatment options and patient populations are more diverse in clinical practice. Off‐label use of rituximab and IV immunoglobulin are common for select patient populations and in certain regions. In addition, unlike the restrictive trial setting, patients may use biologics earlier in clinical practice, which may significantly increase the likelihood of achieving MSE [16, 49]. Although not an endpoint specific to patient symptoms, the RINOMAX trial of newly diagnosed patients reported that early rituximab treatment led to a significantly higher rate of minimal disease manifestation (i.e., QMG ≤ 4 and steroid ≤ 10 mg and no rescue) compared with placebo [67]. Conversely, the BeatMG trial, which primarily included patients with longstanding disease, failed to show efficacy with rituximab for the primary endpoint [68]. These findings are consistent with those from a retrospective study associating earlier use of fast‐acting therapies with faster and more frequent achievement of MM‐5 mg status [16]. This trend also extends to new biologics; in a recent (2025) real‐world study, efgartigimod use in patients with short disease duration (median of 1 year) yielded substantially higher MSE rates than those reported in pivotal trials (74% vs. 40%–55%) [49]. As ongoing studies evaluate novel agents and new data become available, an individualized, early‐intervention strategy may become central to modern gMG care, reshaping expectations for achieving MSE across the patient population.

5
MSE Is a Clinically Meaningful Target
The most robust evidence supporting the clinical benefit of achieving MSE comes from ADAPT [52] and REGAIN [56], which demonstrated that attainment of MSE correlated with substantial improvements in objective, clinician‐assessed measures of muscle strength and fatigability (e.g., QMG and MGC), as well as patient‐reported health‐related QoL (HRQoL) measured with MG‐QoL15r and EQ‐5D. Specifically, among patients who achieved MSE in ADAPT [52, 69] mean improvements from baseline to best recorded scores were 11.4 points for QMG and 16.0 points for MGC. QMG and MGC scores exceeded the minimal clinically meaningful threshold of 3 at 77.1% and 84.8% of all available post‐baseline visits, respectively. When a higher threshold of 5 was applied, these proportions changed to 64.7% for QMG and 75.2% for MGC [69]. In REGAIN and its open‐label extension [56, 64], 85.7% of eculizumab‐treated patients who achieved MSE experienced a clinically meaningful improvement in QMG total score at any time during the trial follow‐up, defined as ≥ 5‐point reduction from baseline.
In terms of HRQoL improvements, ADAPT findings showed that efgartigimod‐treated patients who achieved MSE reached a level of HRQoL comparable to an age‐matched healthy population [69]. These patients met or exceeded the US population norm for the EQ‐5D utility score (0.84) in an average of 61.7% of visits, with a mean best score of 0.96. These participants also met or exceeded the 8‐point MG‐QoL‐15 PASS threshold (total score ≤ 8) in 63.4% of visits, with a mean best score of 2.4 [69]. The significance of this finding is that it directly links the clinical target of MSE with a patient‐defined state of satisfaction. It provides strong evidence that achieving MSE is not just a statistical achievement but reflects a health state that patients themselves consider satisfactory. These results are consistent with findings from a large international survey study of 834 patients with gMG receiving conventional therapy, which reported a strong association between EQ‐5D utility and MG‐ADL scores; mean EQ‐5D utility scores were 0.90 and 0.83 among patients with MG‐ADL scores of 0 and 1, respectively [70].
Although the current evidence is still evolving, collectively, these results suggest that achieving MSE is associated with clinically meaningful improvements in objective physician‐assessed measures and patient‐reported HRQoL, providing initial evidence supporting its use as a patient‐centric treatment target. However, most studies to date had relatively small sample sizes and a lack of systematic comparison between patients who achieved MSE and those who did not. Furthermore, it remains uncertain whether these associations hold consistent across different treatment modalities or extend to long‐term prognosis.

6
MSE Should Be Used in Conjunction With Other Measures to Serve as a Treatment Target
MSE derived from MG‐ADL offers a clear, quantitative, and patient‐centric treatment goal [8], but should not be considered in isolation. Rather, it should be used in conjunction with other clinician‐reported outcome measures, such as MGC and safety‐related parameters in the context of therapy (e.g., dose and duration of steroid therapy), to support a comprehensive, multidimensional assessment of disease activity and therapeutic response in different patient groups.
Several important limitations of MSE should be acknowledged. First, because it is anchored to the MG‐ADL, MSE inherits the constraints of that scale. Despite its widespread utility, the MG‐ADL may not fully distinguish MG‐specific symptoms from comorbidities and does not capture the entire spectrum of disease manifestations, making attribution difficult in some patients. Furthermore, the MG‐ADL is subject to a floor effect, limiting its sensitivity to detect residual symptoms or measure further improvement in patients with mild or well‐controlled disease. The MGNet Clinical Trial Outcome Measure Working Group has recently published detailed administration guidelines for the MG‐ADL, which could help address these challenges [13]. Additionally, the MG‐ADL does not fully capture the heterogeneity of gMG manifestations. A patient could meet the criteria for MSE while still experiencing functionally significant symptoms that are not represented in the MG‐ADL score such as head drop or severe neck weakness. Findings from the SPOON study further highlight this gap, showing that patients with low MG‐ADL scores may continue to report substantial limitations in physical activity, mobility, and energy levels, along with unmet treatment expectations and psychological issues [71]. These considerations illustrate that achieving MSE does not always equate to a truly minimal disease state for every individual.
Second, because MSE is a purely patient‐reported construct, it should be interpreted alongside objective clinical assessments. While several options exist, their practical utility varies. The QMG provides a thorough objective assessment but is often too time‐consuming and burdensome for routine practice, making it better suited for clinical trial settings. Standard manual muscle testing using the MRC scale can be insensitive to the activity‐dependent weakness characteristic of MG. To address this, the Myasthenia Gravis Manual Muscle Test (MG‐MMT) uses a similar framework but with a more granular grading scale adapted for MG. A time‐efficient alternative used at some MG centers is the MGC, which is a hybrid measure integrating some patient‐reported ADL items with objective, clinician‐assessed components (e.g., timed tests for ocular signs, examination of neck and limb strength). This integrated approach supports more accurate assessment, minimizes the risk of misclassification, and enhances individualized, evidence‐informed treatment decisions.
Third, any assessment of treatment success must incorporate safety alongside efficacy. The burden of treatment side effects is highly impactful to patients but is invisible to the efficacy scores used to define MSE. Systematically tracking these issues with standardized measurement tools (e.g., Common Terminology Criteria for Adverse Events, Adverse Event Unit, or glucocorticoids toxicity index) is not yet standard in MG care but would provide a more complete picture of a treatment's overall impact [72, 73]. For example, while corticosteroids remain a mainstay of gMG treatment, long‐term or high‐dose use is associated with a range of adverse effects. To mitigate these risks, both NSIST and biologics are employed as steroid‐sparing agents, although this strategy requires a careful exchange of one potential risk profile for another. NSISTs carry long‐term risks of malignancy, bone marrow suppression, gastrointestinal intolerance, and opportunistic infections, all requiring careful management [74], and each biologic agent has a distinct safety profile that must be considered. Complement inhibitors require pre‐treatment meningococcal vaccination owing to the risk of life‐threatening infection [75], while some FcRn blockers (e.g., batoclimab, and nipocalimab) have been associated with changes in albumin and cholesterol levels, as well as peripheral edema [76, 77, 78]. Additionally, the potential for infections is higher across biologic therapies [79, 80, 81, 82, 83, 84, 85]. Clinicians should also use caution when prescribing agents known to exacerbate MG (e.g., aminoglycosides, fluoroquinolones, macrolides, and statins) and weigh the risk–benefit profile when no safer alternatives are available [5]. A full and diverse treatment armamentarium is essential to achieve the best possible outcome for each patient.
Finally, as summarized in our review of MSE data from clinical trials of newer biologics, a notable proportion of patients did not achieve MSE, even with highly effective therapies (Figure 1). This suggests that while future therapeutic advances and early introduction of biologics may improve MSE achievability, it should not be considered a universal target. As such, treatment goals should remain individualized, guided by disease severity, functional impact, and patient preference.
Taken together, these considerations underscore the importance of using MSE not as a standalone goal, but as part of a comprehensive treatment framework that incorporates objective clinical assessments and safety considerations to ensure both efficacy and tolerability in individualized patient care.

7
Future Directions for Establishing MSE as a Valuable Treatment Goal in gMG
7.1
Defining the Clinical Utility and Prognostic Value of MSE
Future research must systematically compare outcomes between patients who achieve MSE and those who do not to confirm its prognostic value. In particular, research is needed to understand whether achieving MSE predicts long‐term disease stability.
Recent data suggest that approximately one‐third of patients report dissatisfaction with their MG treatment despite measurable symptom improvement [86], underscoring a disconnect between clinical measures and patient‐perceived benefit. To bridge this gap, it is crucial to evaluate the correlation of MSE with broader patient‐centric outcome measures not captured by the MG‐ADL, such as work ability, patient satisfaction, social participation, and emotional well‐being.

7.2
Refining the Concept of Sustained MSE
To fully establish MSE as a meaningful and clinically useful treatment goal, its durability over time must also be considered. However, current assessments are hindered by the lack of standardized definitions, with criteria varying widely across clinical trials (e.g., consecutive weeks versus percentage of total study visits) [60, 62, 87, 88]. Furthermore, achieving continuously sustained MSE represents a high clinical bar given the fluctuating nature of gMG and the influence of comorbidities. This is underscored by published data showing that only a fraction of patients (~30%–50%) who achieved MSE can maintain this state over a prolonged period, depending on the specific criteria used [60, 62, 87].
Consequently, it remains unclear what constitutes a clinically meaningful definition of sustained MSE and, crucially, whether strict continuity offers incremental clinical benefit over achieving MSE with minor fluctuations. Future research must prioritize harmonizing definitions and utilizing clinical trial and real‐world data to determine the most clinically relevant criteria for sustainability.

7.3
Integration of MSE With Other Measures of gMG Symptoms
An MSE‐based treatment goal should incorporate both patient and clinician perspectives to ensure clinical relevance and real‐world applicability, reflect patients' lived experiences, and be feasible to assess in routine care. Accordingly, the clinical utility of MSE in conjunction with other outcome measures should be evaluated by including clinician‐reported metrics (e.g., MGC, MRC, MG‐MMT, or QMG) and safety endpoints. Both clinical trial and real‐world evidence will be critical in determining whether MSE is a reliable and actionable target in routine practice. Structured interviews or surveys with patients and clinicians may offer important insights into the perceived value of MSE and similar integrated measures in clinical care. These perspectives could support the development of consensus‐driven guidelines for incorporating MSE into routine practice.

8
Conclusions
Given the widespread use of MG‐ADL in both clinical and real‐world studies of gMG, MSE has emerged as a valuable, patient‐centric measure of minimal disease manifestation and may help support greater standardization of treatment goals based on minimal symptom burden. As the gMG treatment landscape continues to evolve, understanding the feasibility, durability, and prognostic value of MSE will be key to defining its role in treatment planning. Further research is needed to validate its clinical relevance, determine the duration required for a meaningful clinical impact, and optimize its integration with other outcome measures in routine practice.

Author Contributions

Akiyuki Uzawa: conceptualization, writing – review and editing, investigation, methodology, supervision. Dustin Nowacek: conceptualization, investigation, methodology, supervision, writing – review and editing. Andreas Meisel: conceptualization, writing – review and editing, investigation, methodology, supervision, project administration. Cynthia Z. Qi: conceptualization, investigation, methodology, supervision, data curation, writing – original draft, writing – review and editing. Jeff Guptill: conceptualization, investigation, methodology, supervision, writing – review and editing. James F. Howard Jr: conceptualization, investigation, methodology, supervision, writing – review and editing.

Funding
This work was supported by Argenx.

Ethics Statement
This review only synthesized previously published data. Therefore, ethical review was not required.

Conflicts of Interest
Akiyuki Uzawa has received honoraria from Alexion Pharmaceuticals, UCB, Chugai Pharma, Novartis, and Argenx. Andreas Meisel received fees as a speaker or consultant and trial site compensation/financial research support (paid to his institution) from Alexion/AstraZeneca Rare Disease, Amgen, Argenx, Axunio, Desitin, Genpharm, Grifols, Hormosan, Immunovant, Johnson & Johnson, Merck, Neopharm, Novartis, Octapharma, Regeneron, Sanofi, and UCB. He is a member of the Medical Advisory Board of the German Myasthenia Society. James F. Howard has served on advisory or data safety monitoring boards for argenx, Regeneron, Alexion, Amgen (Horizon), Novartis, Biohaven, Cartesian Therapeutics, CorEvitas, Merck EMD Serono, Seismic Therapeutics, and UCB Biosciences; has served on speakers bureaus for Academic CME, PeerView CME, Platform Q CME, Medscape CME, and MJH LifeSci; holds stock in Johnson & Johnson and Pfizer, with immediate family holdings in GlaxoSmithKline; and has received institutional research support from Alexion, argenx, UCB, NIH, CDC/RTI, Duke University (DCRI), Cartestian Therapeutics, NMD Pharma, and Ad Scientiam. He also serves in non‐compensated roles with the Myasthenia Gravis Foundation of America and the American Association of Neuromuscular and Electrodiagnostic Medicine. Cynthia Z. Qi, Dustin Nowacek, and Jeff Guptill are employees of Argenx and own stocks of Argenx.

Supporting information

Table S1: Open‐label extension trials of FcRn inhibitors and complement inhibitors with MSE reported.