Physician-Reported Perspectives on Myasthenia Gravis in the United States: A Real-World Survey

Myasthenia gravis (MG) is a debilitating, chronic, autoimmune, neuromuscular disease with most patients experiencing fluctuating muscle weakness and fatigue [1, 2]. MG is caused by pathogenic immunoglobulin G autoantibodies, which can inhibit signal transmission at the neuromuscular junction (NMJ) by binding to various proteins including receptors [3‐5]. Approximately 74–88% of patients have acetylcholine receptor (AChR) autoantibody-positive MG. Synaptic transmission to muscle fibers is impacted by these pathogenic autoantibodies that, by binding to receptors, block acetylcholine and increase receptor degradation. Additionally, AChR autoantibodies trigger the classical complement cascade, which converges at complement C5, leading to damage of the NMJ, and ultimately impairment to muscle contraction [6].

MG is a rare disease, with an estimated 60,000 cases of MG in the United States (US) [7, 8]. As with many rare diseases, because of the relatively low prevalence compared with more common diseases, there is a lack of real-world studies in MG to understand and address patients’ unmet needs and the burden of disease [9]. While randomized clinical trials are necessary to obtain robust efficacy and safety data on a treatment, observational real-world studies are also important as they can provide information on larger, more representative populations compared with clinical trials, and an understanding of the true progression and management of the disease [9]. An analysis of insurance claims between 2010 and 2019 from the IBM® MarketScan® database showed that 91% of patients living with MG in the US received drug therapy, and 40% of those received non-steroidal immunosuppressive treatment (IST) or biologics [10]. However, some survey research has suggested that as many as 50% of patients with MG fail to reach minimal symptom expression (Myasthenia Gravis Activities of Daily Living score 0 or 1) [11], while more stringent criteria for refractory disease has been estimated at 10–20% of the MG population [12, 13]. Inadequately controlled disease is more likely to have significant impact on prognosis, health-related quality of life, and use of healthcare resources compared with the nonrefractory MG population [3, 13‐15]. Hospitalizations, myasthenic crises, and use of acute treatments for MG worsening such as IVIg and PLEX are key drivers of increased MG-related healthcare costs [16]. Despite these insights, comprehensive data are still lacking on real-world clinical experiences and perspectives from a large sample.

Adelphi Real World Disease Specific Programmes™ (DSPs) are an established methodology for investigating treatment practices across a large range of diseases using point-in-time surveys [17]. They collect real-world data from clinical practice, including patient demographics, treatment practices and physician-reported healthcare resource utilization (HCRU) [9].

Here, using data from the MG DSP, we aimed to provide comprehensive real-world insights and evidence into the HCRU, management and disease burden of MG in the US.

Drawing on a real-world sample of consulting physicians and presenting patient populations, these data obtained from the Adelphi Real World MG DSP provided valuable insights into the management of MG in the US.

Our data show that, on average, patients waited approximately 9 months for a diagnosis from their onset of symptoms, which could have left them untreated and thus at risk of acute deterioration of symptoms and development of myasthenic crisis [20, 21]. Delays in diagnosis can be due to the fluctuating nature of MG symptoms, making MG difficult to diagnose on clinical examination. Diagnoses may also be missed in primary and non-neurology specialist care as patients can have normal serology and electrophysiology results, particularly in ocular MG, suggesting there is a need for education in primary care and of non-neurology specialists, and more reliable methods of detection [20, 21]. Some patients also experienced unnecessary, non-specific investigations, leading to a mean delay of approximately 5 months from first symptom to consultation with a specialist consultant. MG is also under-recognized in elderly patients due to symptoms such as fatigue and slurred speech falling under broader illness symptoms and thus patients only being referred to non-specialist clinicians [21]. Our study found that approximately 1 in 5 patients were initially misdiagnosed, which may have increased the burden of disease for patients [20].

The number of symptoms reported at diagnosis and after treatment was used as a measure of impact of treatment on disease burden, and as the mean number of symptoms per patient was the same after treatment as it was at diagnosis, many patients may still have been impacted by various aspects of the disease, despite treatment. This suggests that treatment does not necessarily reduce patient burden, even though some of these symptoms will be different than at diagnosis. This is supported by several studies highlighting the fact that many people with generalized MG still report a negative impact of disease or treatment and report fatigue [22, 23], muscle weakness, anxiety and depression, despite receiving treatment [24‐30]. However, whilst many of the symptoms were MG-specific, some such as general fatigue could also be attributed to other comorbidities. Ocular myasthenia was found to be the most frequently reported symptom and general fatigue was the most “troublesome” symptom, with 60% of symptoms at time of survey completion reported as moderate or severe. The burdensome nature of general fatigue may be common, as observational studies report a similar correlation between the increase in disease severity and an increase in fatigue score [31, 32]. The proportion of patients with more than just ocular symptoms (MGFA Class II–V) increased following diagnosis and throughout the course of disease, demonstrating progression from ocular MG to generalized MG, which is likely to negatively impact patients’ quality of life [2].

Among patients with moderate-to-severe MG (MGFA Class III and above) nonsteroidal ISTs were the most prescribed treatment class, while one-third of patients in these classes required chronic steroids. In addition, over one-third of the patients in our survey required acute treatment at some point, predominantly for the treatment of exacerbations or myasthenic crisis, highlighting the lack of disease control with current maintenance treatments or regimens. About 10% of patients have also used acute treatment as bridging therapy due to slow onset of action of some available maintenance or chronic therapies. This finding supports data from the US medical claims database (IBM® MarketScan® Commercial Claims and Encounters) showing that, while receiving AChEI and/or steroids, 27% of patients experienced exacerbations and, of these, 38% of patients required IVIg rescue therapy [10]. Patients with more severe disease require more consultations and have more hospital admissions, placing additional burden on patients and healthcare resources, while disease burden is further exacerbated by limitations of current treatment, such as toxicity and delayed onset of action [32].

The development of new agents with selective immunological targets and rapid onset of action, such as complement inhibitors (eculizumab, ravulizumab, zilucoplan) and neonatal Fc receptor blockers (efgartigimod, rozanolixizumab, nipocalimab) that, while real-world clinical experience is needed to understand whether these drugs will fulfil their potential, may help to resolve these limitations of current treatments and, ultimately, have a positive impact on the burden of disease in patients with MG [32]. In addition, increased use of SCIg in place of IVIg may be beneficial to reducing hospital admissions for IVIg. In our survey, the second most common reason (21.7%) for hospital admissions was for receiving IVIg, thus self-administered treatment at home may help to reduce this burden for both patients and the healthcare system. Continued disease burden and high healthcare cost is, unfortunately, a familiar issue in the US. Real world data on treatment patterns and HCRU show high burden and high cost for a wide range of diseases [33‐35], and while the development of new MG treatment options is therefore of benefit, they are unlikely to fully resolve the issues identified in our study.

Inherent limitations to data collection via questionnaires apply to this study, including missing fields and answers dependent on either physicians’ perception or patients’ memory. As a result, there was some variation in the total number of patients per variable. Data capture was dependent on patients presenting within the fieldwork time frame, in which, while generating data for a range of patients across treatment types and disease stage, some patients may have consulted or presented more frequently than others. In addition, not all physicians in this survey were neurologists, and, therefore, the practices of primary care physicians or geriatricians may have not been fully representative of how MG is treated by specialists, especially in more complex cases. However, minimal inclusion criteria and the inclusion of non-neurologists aim to ensure that a broad population of physicians, other HCPs and patients, and therefore perspectives, is captured. Physician and patient participation is influenced by willingness to participate in the research and practical considerations of geographic location. In addition, our aim was to give a broad picture of MG patients in general, not only those treated at specialized centers. Follow-up studies of this nature that dive deeper into specialist providers and patient subpopulations will be even more beneficial. Patient-reported outcomes are a useful measure to assess the impact of treatment, however, due to the nature of this point-in-time study, patient-reported outcomes were only collected at the time of the survey and were not captured at diagnosis for a comparison to before MG treatment initiation. The majority of the patients included in our survey were reported to have at least one comorbidity, a small proportion of whom were using over-the-counter medication or supplements in addition to their MG treatment. Some of these over-the-counter medications, such as quinine and magnesium, have been shown in some instances to exacerbate MG [36]. In addition, the mean age at diagnosis was relatively high compared with the expected age of MG onset, [37, 38]. Thus, it is possible that a subgroup analysis of a younger population with fewer comorbidities may have yielded different results. Furthermore, with the data collection occurring during the 2020 coronavirus pandemic, face-to-face consultations may have been restricted and healthcare resources reduced. Finally, as MGFA classification is used predominantly in clinical trials and not routinely in clinical practice, the applicability of the disease severity data may be limited.

Despite these limitations, real-world studies in MG are vital for the understanding of the impact of disease burden on patients living with MG.

Overall, these real-world data suggest that a proportion of patients with MG in the US had a significant need for improved disease management. This is consistent with additional real-world evidence from US claims databases that has identified an unmet need for improved treatment options in MG to reduce the disease burden placed upon patients and healthcare resources.