gMG is an autoimmune-mediated neuromuscular junction disorder1(superscripted). Notably, the disease is more common in Caucasian population2 and typically affects the postsynaptic proteins at the muscle end plate in approximately 80-90% of gMG cases3. Considering the detrimental effects of the disease on patients and their quality of life (QoL), this literature aims to divulge into different aspects of gMG in order to understand the current treatment deficiencies in gMG.
Myasthenia gravis (MG) is an autoimmune-mediated neuromuscular junction disorder that manifest as fluctuating weakness and fatigability. The estimated incidence rate of MG is around 4-30 cases per million person-years, with prevalence rates ranging between 150-200 cases per million people in Europe1. Locally, the prevalence of MG is around 60 cases per million, which is considerably lower those seen among Caucasian populations2. Notably, the disorder is caused by autoantibodies directed against postsynaptic proteins at the muscle end plate, mainly the acetylcholine receptor (AChR), which affects approximately 80-90% of patients. Nevertheless, some patients may harbour antibodies against the muscle-specific tyrosine kinase (MuSK) and patient with this type of antibodies may exhibit more focal muscle symptoms with wasting in regions of the neck, shoulder, facial and bulbar-innervated muscles. Furthermore, MuSK-MG predominantly affects females in their fourth decade3. Clinically the disease can be classified into either ocular MG (oMG) or generalised MG (gMG)4.
Undeniably, patients with gMG often experience a wider range of symptoms than patients with oMG and these can potentially manifest as recurrent exacerbation or as myasthenic crisis where mechanical ventilation remains a mainstream treatment. Traditionally, patients with gMG are treated with pyridostigmine and immunomodulators such as corticosteroids and azathioprine or mycophenolate mofetil (MMF). During the acute flare up, particularly in myasthenia crisis, treatment comprises of intravenous immunoglobulin (IVIG) or plasma exchange (PLEX)4. Despite these treatments, the unmet treatment needs in gMG persist as gMG patients often experience a poor quality of life (QoL)5 and often experience adverse events associated with the treatment6. The problem is further compounded by the lack of a specific gMG biomarkers7, thereby, preventing clinicians to determine the disease course or assess the drug response exhibited by patients on treatment.
Patients with gMG are often unable to participate in activities of daily living (ADL) in the same way as they did prior to the diagnosis, mainly due to the muscle weakness. Interestingly, these findings were corroborated by the Task Force of the Medical Scientific Advisory Board of Myasthenia Gravis Foundation of America (MGFA) in 2000, where they recognised the difficulties faced by gMG patients who often reported a poor QoL; thus, the advisory board meeting recommended clinicians to consider using MG-specific tools to evaluate the effects of gMG on patient’s QoL8. Although the aim of MG treatment is to minimise the disease burden, induce remission, some gMG patient may still experience mild weakness without functional limitations5. Compounded by these overwhelming issues, recent studies have shown a strong correlation between mental health disorders and MG. In fact, up to one-third of MG patients are diagnosed with depression, and those with even milder forms of disease are still likely to experience mental health impairment9.
To make matters worse, MG patients often have an unpredictability disease course, and poor prognosis despite having different treatments. To understand the real impact of MG, Dewilde et al., (2023) analysed the findings from two major observational studies (MyRealWorld-MG [MRW], and the General Population Norms [POPUP]). MRW included 1,859 adult patients from 9 countries, diagnosed with MG, whereas the POPUP included 9,000 members of the general public from 8 countries. Astonishingly, the analysis revealed that utilisation of medical care was twice as common in the MRW study compared to the POPUP study (51.9% vs 24.6%, respectively). Similarly, MRW cohorts were 2.6 times more likely to take sick leave compared to POPUP cohorts (34.4% vs 13.2%, respectively). Furthermore, MG patients required 4 times more support from their caregivers compared to the normal population (34.8% vs 8.3%, respectively)10. These findings highlight the seriousness of the condition, in addition to the detrimental effects of the disease has on individuals, regardless of their demographics.
High medication prices are likely to drive medication non-adherence. Furthermore, the medication price increase in recent years has far outpaced the rate of inflation and treatment innovation or research and development spending11. This was precisely highlighted in a recent survey performed by PatientView among 339 neurology patient groups. The aim of this survey was to analyse the patient perception towards pharma spending on neurological disorders. Surprisingly, 52% of neurology patient groups reported an inadequate investment by the pharma industry on nervous system disorders, with only half of the neurology patient groups expressing that they may exert influence on drug research and development compared to 69% of blood-cancer patient groups12. This revealed how little is being invested by the pharma industry on neurological disorders and how uncertain patients with neurological disorders feel about their disease prognosis. Apart from pharma investment, diagnosis of gMG also remains challenging since muscle weakness, fatigue and other symptoms may be erroneously ascribed to other known disorders such as Lambert-Eaton myasthenic syndrome.
In addition, the fluctuating nature of these symptoms and the presence of comorbidities may complicate the diagnosis further13. Together, these factors may delay the actual diagnosis and referral to appropriate specialist. The issues related to diagnostic delay was explored further by Andras et al., (2024) in a study that evaluated the mean duration of diagnosis delay among patients with MG from five European countries and explored the impact of more than 1 year diagnosis delay. The study included a total of 386 patients from Europe* and diagnosis delay (time from symptom onset to diagnosis) was calculated and described as patients experiencing diagnostic delay of >1 year and ≤1 year. Interestingly, the mean diagnostic delay was 361.1 days and around 27.1% of patients experienced a diagnostic delay for >1 year. Astoundingly, 69.2% of patient with >1 year of diagnostic delay initially received a different diagnosis compared to only 17.4% of patients who experienced diagnostic delay for ≤1 year. More worryingly, 30.5% of patients with diagnostic delay of >1 year suffered from anxiety and 21.9% had depression compared to only 17.4% patients experienced anxiety and 13.1% experienced depression in the diagnostic delay by ≤1 year group. These findings demonstrated that more than a quarter of MG patients experience a diagnostic delay by >1 year and this may further exacerbate their symptoms, and worsen their QoL13.
22% of MG patients are at risk of developing another autoimmune disease (AD) during their lifetime, compared to only 9% in an age-and sex-matched control group14. Autoimmune diseases such as thyroiditis, systemic lupus erythematous (SLE), rheumatoid arthritis, type 1 diabetes, Addison’s disease, dermatopolymyositis and neuromyelitis optica are the most commonly associated ADs with MG. However, the effects of other AD comorbidities on the prognosis of MG and treatment response remained unclear until a retrospective single-center cohort study performed by Laako et al., (2021) evaluated this relationship in 154 thymectomised gMG patients, with a mean follow-up time of 8.6 years post-thymectomy. Comorbidities diagnosed at any timepoint were retrieved from medical records and Charlson comorbidity index (CCI) score were calculated. Patients were initially divided into two subgroups, mainly the MG alone group (n=45) and the MG with any comorbidities group (n=109). The MG with any comorbidities group was further categorised into MG with other ADs (n=33) and MG with non-AD comorbidities (n=76). The endpoints analysed were the compete stable remission (CSR), minimal need for medications, and need for in-hospital treatment.
The study found that CSR was more frequent in MG alone compared to MG with any comorbidity group (26.7% vs 8.3%, p=0.004). Furthermore, the need for in-hospital treatment was lower in the MG alone group than in MG patients with any comorbidity (p=0.046). Lower CCI scores were prevalent in both patients with minimal need for medication and in patients who did not need in-hospital treatments (p<0.001). The study concluded that patients with gMG and comorbidities have a poorer prognosis than patients with MG alone post-thymectomy. However, having AD comorbidities may not increase the risk compared to patients with non-AD comorbidities15.
Considering gMG patients, particularly those with comorbidities often require hospital admission, Zhdanava et al., (2024) used the database of 2,739 patients with and without gMG from 2017-2021 to demonstrate the incremental healthcare cost and resource utilisation (HRU) associated with gMG and its common comorbidities. Unsurprisingly, the study revealed that gMG was associated with a substantial incremental cost and HRU. Moreover, the cost increased by 20% and 34% among gMG patients with cardiometabolic and psychiatric conditions, respectively (Figure 1)16. In light of this, it is important for clinicians to evaluated and manage gMG along with its comorbidities in order to reduce any future acute exacerbations. In summary, gMG is a complex disease that requires a multimodal approach, and more research is required to improve the management of gMG, especially from the therapeutic point of view.
.jpg)
Figure 1. Mean all-cause healthcare cost (2021 USD) during the follow-up period, per-patient-per-month by comorbidity and disease profile subgroup16. ED, emergency department; gMG, generalised myasthenia gravis; IP, inpatient; OP, outpatient; USD, United States dollar.
* France/Germany/Italy/Spain/United Kingdom13.
References
1. McCallion J, et al. BMC Neurology 2024; 24(1): 61. 2. Chan KH. An update on myasthenia gravis. 2004. 3. Borges LS, et al. Front Immunol 2020; 11: 707. 4. Tan JY, et al. J Clin Neurol 2024; 20(4): 412-21. 5. Wu X, et al. Front Neurol 2022; 13: 1072861. 6. Bacci ED, et al. BMC Neurol 2019; 19(1): 335. 7. Kaminski HJ, et al. Ann N Y Acad Sci 2012; 1275(1): 101-6. 8. Aggelina A, et al. J Pers Med 2023; 13(7). 9. Dewilde S, et al. BMJ Open 2023; 13(1): e066445. 10. Dewilde S, et al. Advances in Therapy 2023; 40(10): 4377-94. 11. Sertkaya A, et al. JAMA Netw Open 2024; 7(6): e2415445. 12. PATIENTVIEW. WHAT 339 NEUROLOY PATIENT GROUP SAY ABOUT PHARMA IN 2023-24. 2024. 13. Cortés-Vicente E, et al. Annals of Clinical and Translational Neurology 2024; 11(9): 2254-67. 14. Fang F, et al. J Intern Med 2015; 277(5): 594-604. 15. Laakso SM, et al. Journal of the Neurological Sciences 2021; 427. 16. Zhdanava M, et al. Current Medical Research and Opinion 2024; 40(7): 1145-53.
