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Immunopathogenesis and Treatment of Myasthenia Gravis

Info: 3787 words (15 pages) Essay
Published: 8th Feb 2020 in Biology

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Abstract:

Myasthenia gravis (MG) forms the largest disease group of neuromuscular junction disorders and it is characterized by pathogenic autoantibodies against components of the post synaptic endplate of the neuromuscular junction (NMJ). Acetylcholine receptor antibodies are the most prominent mechanism of action causing MG, however other components of the NMJ play a role in the pathophysiology of this disease. Determining the pathophysiology of this disease helps determine the subgroup of MG. This categorization dictates the course of treatment for each individual patient. This paper will analyze the various treatment methods associated with MG and review their course of action on a cellular level. The most common treatment methods for MG include pharmacologic methods with the primary ingredient being acetylcholinesterase inhibitors or steroids to control the immune response (Mickelson Lecture 2). Other methods can be utilized based on the severity of the patient’s symptoms. Given that MG is extremely variable from patient to patient, it is not possible to have a generalized treatment method. However, many patients with MG are characterized under the subgroup called ‘generalized’ and have autoantibodies against the acetylcholine receptors (AChR). Considering this, it is worth analyzing treatment methods that focus on the AChR versus other components of the NMJ. Additionally, intravenous immunoglobulin (IVIg) treatment infusions can be considered a viable option to treat this subgroup. A more radical approach to treat MG is a thymectomy which removes a portion of an abnormal thymus seen in patients with MG and AChR autoantibodies. This procedure is completed to reduce hyperactivity of the thymus, reduce overproduction of immune response cells and has been shown to produce favorable outcomes when coupled with pharmacologic agents. After analyzing this treatment method and IVIg, it was concluded that both thymectomy coupled with prednisone and IVIg treatment have produced positive results.

Introduction:

MG is a neuromuscular disease of the NMJ in muscle. More specifically, MG is an autoimmune disease where pathogenic autoantibodies produced by the thymus disrupt components of the postsynaptic muscle endplate. Specific autoantibodies act against the following components of the NMJ in the postsynaptic membrane, acetylcholine receptors (AChR), muscle specific kinases (MUSK), lipoprotein-related protein 4 (LRP4), and agrin. AChR antibodies are highly specific to MG patients and their presence along with muscle weakness confirms the disease (Phillips & Vincent, 2016). Further diagnostic evaluation is necessary to define the subgroup and severity of this disease. The presence of certain diagnostic markers, pathogenic factors, and autoantibodies help match patients into the various subgroups. Biochemical diagnostic methods used to analyze the presence of such markers include radio-immunoprecipitation, ELISA and immunofluorescence for AChR, MUSK and LRP4 autoantibodies. Subgroups based on serum antibodies and clinical features include generalized (AChR antibody-positive MG), early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of MG (Aydin et al., 2017). Additionally, research suggests that agrin-associated myasthenia gravis might emerge as a new subgroup (Zhang et al., 2014). 

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ACh receptor-related MG is characterized as the most common form of autoimmune myasthenia with 80% of patients having this generalized subgroup. The mechanism of this form of MG results in destructive damage to the end plate membrane by an immune response produced by the thymus (Phillips & Vincent, 2016). The connection between immune system cells and cytokines is a highly researched topic of study for understanding the mechanism of generalized MG as well as for possible treatment methods. Thymic abnormalities in ACh receptor-related MG is still not fully understood.

MuSK-related MG primarily differs from ACh-related MG in that patients experience increased muscle weakness and increased degradation of muscle tissue. Patients with MuSK-related MG are significantly less common with only 10% of MG patients containing abnormalities with MuSK (Huijbers et al., 2019). Analysis of MuSK-related MG has been influential in analyzing the mechanism and importance of MuSK in the NMJ. These findings illustrate that MuSK plays a role in maintaining the structure and function of postsynaptic and presynaptic components of mature NMJ.

Low-density lipoprotein receptor-related protein (LRP4)-related MG is not as well defined and is emerging as a new mechanism of MG with the remaining 10% of patients having abnormalities with these autoantibodies (Le Panse & Berrih-Aknin, 2018). LRP4 has been identified as the agrin receptor where agrin acts as the ligand. This binding event activates MuSK production and leads to the formation of AChR aggregation in the NMJ (Zhang et al., 2014). 

Confirming the subgroup of MG for patients will dictate the specific treatment method utilized. Typical treatment methods include acetylcholinesterase inhibitors or steroids to control the immune response (Mick Lecture 2). In more severe cases a thymectomy may be suggested, otherwise the typical mode of treatment includes immunosuppressants, dietary restrictions and in special cases immunotherapies such as IVIg treatment through complete blood transfusions (Jordan & Freimer, 2018). After analyzing the treatment method outcomes, I propose that the more radical thymectomy with pharmacological treatment produces the best patient treatment outcomes. This method along with IVIg will be analyzed to assess their significance in treating generalized MG.

This topic relates to me personally. I have a teammate on the University of Minnesota Women’s hockey team who was diagnosed with MG after surprise brain surgery for a significant cyst. The stress and environmental factors triggered her dormant MG and she has been battling against her symptoms for the past two years’. Amazingly, she could return to play after intense lifestyle changes and extensive treatment. She found success using a cocktail of pharmaceutical agents, with prednisone being the dominant agent improving her symptoms and eventually she was approved for IVIg treatments. She has had a total of three different transfusion treatments and will be weaning herself off her intense medication list and pursuing a thymectomy for hopeful improvements. The thymectomy is not a guaranteed procedure with an unknown success rate that is dependent on many different variables. In addition to this topic having a personal correlation to my life, it also relates in that I am an athlete and understand the importance of optimal health for peak performance. I will be applying to medical school in May and would like to continue in the field of sports medicine or orthopedics. I am extremely intrigued at muscle function and muscle disease as well as treatment for such diseases so that everyone can experience the joy of sport or life in general. 

Results:

The data presented by Eienbröker, Christian, et al., illustrates a IVIg treatment trial that measures the changes in quantitative myasthenia gravis (QMG) score of chronic and insufficiently controlled MG patients under standard immunosuppressant therapy and symptomatic treatment. This study contained sixteen patients (6 men, 10 women) with a mean age of 59.3 ± 20.8 years. All of patients met the parameters of being categorized with generalized MG, effects all muscles plus AChR antibody positive, and did not respond to immunosuppressant’s. The patients were treated with an initial loading dose of IVIg (0.4 g/kg body weight/day for 5 consecutive days). Afterwards, additional booster dose infusions (0.4 g/kg body weight/booster dose every 4–12 weeks) were given as long‐term maintenance therapy. IVIg treatment effects on MG patients were measured using quantitative MG (QMG) scores, MG efficacy score (MGES), and clinical exacerbations. The QMG test is a clinical assessment of MG severity, a sample test is provided in the supplemental material for reference. MGES is an arbitrarily combined sum score that measures the efficacy of the IVIg treatment and, based on the score, indicates subjective measures of endpoints to evaluate outcomes in symptoms. This is evaluated to determine whether the results are measuring IVIg treatment outcomes.  Clinical exacerbations are characterized as side effect caused by MG and help analyze the symptomatic effects that IVIg treatment has on the patient. Additionally, the researches completed IVIg treatments in conjunction with cholinesterase inhibitors (CH) and prednisone (PR) to compare with the IVIg treatment group which is given by Figure 1A. Baseline measurements and treatment measurements after 24 months in the 5 different experimental groups are given for analysis.

The results in terms of CH dose, QMG score, PR dose, frequency of clinical exacerbations, and MGES are shown in Figure 1. The CH and PR dose correspond to the cholinesterase inhibitor and prednisone dosages used before and after IVIg treatment and the figure illustrates the dosage of CH or PR needed to maintain MG treated symptoms over a 24 month period. According to Figure 1, the PR experimental group (1C) had positive results on patients with IVIg treatment in conjunction with steroid use. This group resulted in improved MG maintenance with decreased dosages of steroid, PR, after being treated with IVIg immunotherapy.  From baseline to 24 months a decrease in PR dosage is seen to maintain MG symptomatic suppression and overall improve the patient’s quality of life. This data produced more statistically significant results based on p < 0.0073* compared to the CH group (1E) whose results are inconclusive and no interpretation can be made from this plot. Data in Figure 1 resulted in improved QMG scores (1A) and MGES scores (1B) for the IVIg treatment groups based on the average scores and the statistically significant p < 0.0001* and p < 0.0012* indicating that this treatment method is a useful technique to symptomatically treat MG long term.

Figure 1: Changes in clinical and preclinical endpoints before and after 24 months of IVIg maintenance therapy. Boxplots are shown with means and their respective whiskers of the combined endpoint QMG score (A), MGES (B), Prednisone dose (C), myasthenic exacerbations (D), and cholinesterase inhibitors dose (E).

The data presented by Wolfe, G et al., illustrates a MGTX extension study, in which a 60-month (5 year) study was completed on the therapeutic effects that prednisone in conjunction with a thymectomy has on MG patients. The original MGTX study was an international, rater-blinded study completed at 36 academic medical centers across 15 different countries. Patients were screened to meet a strict criterion consisting of the subcategory generalized non-thymoma MG and who had this disease for less than five years. Additionally, the patients that met these criteria had to be between the ages of 18-65. Serum tests of AChR antibodies were analyzed during this screening process to confirm the MG subgroup. The same participants were used for the extension study illustrated in Figure 2. A random 1:1 assignment of either extended transsternal thymectomy plus prednisone or prednisone alone was established and the same dosage of prednisone was given to both groups. The results are given in Figure 2.

 The data resulted in improved outcomes in the prednisone plus thymectomy treatment group. These benefits include improved disease outcomes, reduced prednisone requirements, and fewer hospitalizations for the disease exacerbations compared with prednisone alone.  

Figure 2: Mean Quantitate Myasthenia Gravis score (A) and mean alternate-day prednisone dose (B) by treatment group during the 5-year study period. Error bars represent SEs.

Data provided by Calhoun et al., illustrates a meta-analysis of pooled thymectomy procedure outcomes. Table 3 illustrates the complexity of the procedure and the outcomes that can occur from it. However, the results do indicate consistency across multiple trials. When comparing the results between the two groups, there was an 11 year gap between the subjects and a difference in the number of patients receiving preoperative corticosteroids (33% vs. 11%). The corticosteroid dosage seems to be the only factor that is altered by the physician and when analyzing the difference between groups, there is an overall negative impact on current patients compared to the previous group. This is specifically notable in the percentage of improvements/no improvements, patients with no generalized weakness and patients in complete remission (Table 3). Again, the dosage amount was dependent on the severity of the patient’s symptoms and the treatment is subjective to that patient’s unique symptoms so it is hard to make a general statement or claim of causation. Lastly, the data suggests that 71% of current patients and 88% of previous patients experienced no generalized weakness and 46% of current patients and 52% of previous patients experienced complete remission which is relatively consistent across trials (Table 3).

Table 3: Comparison of results provided by multiple thymectomy experiments. Pooled data was recorded in Calhoun et al., 2016.

Discussion:

 Myasthenia Gravis is a disease whose pathophysiology is still being understand. Most patients that have MG are categorized as generalized, with the primary autoantibody attacking the NMJ being AChR related and having generalized muscle weakness. As discussed in class, the most common treatment methods for MG include pharmacologic methods with the primary ingredient being acetylcholinesterase inhibitors or steroids to control the immune response (Mickelson Lecture 2).

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After analysis of pathophysiology and therapeutic approaches, it is difficult to propose a definite advantage of one procedure over the other. However, promising results have been established for thymectomy plus prednisone treatments. Based on the data in Figure 2, a clear positive correlation is visualized with treatment and improved outcomes. These improved outcomes include overall disease outcomes, reduced prednisone requirements, and fewer hospitalizations for the disease exacerbations compared with prednisone alone. Even though thymectomy procedure outcomes are not completely standardized and vary depending on the patient and their subgroup of disease, Table 3 provides promising data that there is at least a correlation over time of improved symptoms and improved MG management with this procedure.

Additionally, the IVIg treatment outcomes outlined in Figure 1 illustrate positive results as well. Based on plots A and B of figure 1, which both illustrate the outcomes of IVIg treatment in the absence of additional pharmaceutical treatment, there is an overall decrease in MG symptoms after 24 months. However, IVIg treatment plus PR pharmaceutical agent produced more statistically significant results based on p < 0.0073* and improved outcomes with a lower average treatment requirements after 24 months. These results seem to be biologically significant and promising for further treatment of MG patients characterized in the generalized subgroup. Still other studies need to be completed to further improve the data and to analyze the effects that this treatment has on other subtypes of MG.

Conclusions/Future Prospects:

Overall the complexity of this disease is extensive and is still undergoing research to fully understand all its components. Therefore, understanding the subtype and specific mechanism for each patient is extremely important to determine their course of treatment. With generalized MG containing 80% of the effected population, it is important to analyze this subgroup more so that a greater population of diseased individuals can be treated. Based on the data presented in both the IVIg trial and the MGTX extension trial, it is difficult to conclude which form of treatment produces the best results. In both trials, positive treatment outcomes were seen. However, they cannot be directly compared to each other because they are assessing different variables. Based on this data, however, both methods produce positive treatment options for patients with generalized MG. Utilizing either of these methods may have beneficial effects. Future studies still need to be completed to help combat this disease and improve basic knowledge of its extensive pathophysiology.

The conclusions made from Figure 1 are strong in some areas but weak in others. I think that the graph is very difficult to read and the methods described in the paper are extremely vague. The author could have done a better job at explaining the MGES scores and improved the data. To improve Figure 1 and make it easier to interpret, all of the dependent variables could have been made the same and could have measured QMG scores. However, it is strong in that a clear, statistically significant correlation is seen with reduced negative symptoms, QMG score and decreased prednisone dosage requirement after IVIg treatment. I learned that IVIg treatment is an effected mode of MG maintenance therapy and that the treatment is unique to each patient. Additionally, the conclusions made in Figure 2 and 3 are very strong. I think that Figure 2 clearly illustrates an improvement in patient’s symptoms in both treatment groups, but more specifically in the thymectomy plus prednisone group. Even though a positive correlation is seen again, it is important to note that treatment is unique to each patient and the outcomes are different depending on the pathology that the patient presents. However, Figure 3 clearly illustrates that the results are relatively consistent across the current and previous data outcomes of MG patients that underwent the thymectomy procedure. This provides promising data, that even though the treatment is unique to each individual, it can still be beneficial. Overall, I learned that MG is a unique neuromuscular disease that presents with many pathologies and more are still being discovered. From first-hand experience, I have learned how difficult it can be on someone’s life and taxing list of medications required to maintain a normal life.

References:

  • Aydin, Y., Ulas, A. B., Mutlu, V., Colak, A., & Eroglu, A. (2017). Thymectomy in Myasthenia Gravis. The Eurasian journal of medicine49(1), 48–52. doi:10.5152/eurasianjmed.2017.17009
  • Calhoun, R. F., Ritter, J. H., Guthrie, T. J., Pestronk, A., Meyers, B. F., Patterson, G. A., … Cooper, J. D. (2016). Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients. Annals of surgery230(4), 555–561.
  • Eienbröker, Christian, et al. “Intravenous immunoglobulin maintenance treatment in myasthenia gravis: a randomized, controlled trial sample size simulation.” Muscle & nerve 50.6 (2014): 999-1004.
  • Huijbers, M. G., Vergoossen, D. L., Fillié-Grijpma, Y. E., van Es, I. E., Koning, M. T., Slot, L. M., … & Verschuuren, J. J. (2019). MuSK myasthenia gravis monoclonal antibodies: Valency dictates pathogenicity. Neurology-Neuroimmunology Neuroinflammation6(3), e547.
  • Jordan, A., & Freimer, M. (2018). Recent advances in understanding and managing myasthenia gravis. F1000Research7, F1000 Faculty Rev-1727. doi:10.12688/f1000research.15973.1
  • Kaminski H.J. (2018) Treatment of Myasthenia Gravis. In: Kaminski H., Kusner L. (eds) Myasthenia Gravis and Related Disorders. Current Clinical Neurology. Humana Press, Cham
  • Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res. 2016;5:F1000 Faculty Rev-1513. Published 2016 Jun 27. doi:10.12688/f1000research.8206.1
  • Le Panse R., Berrih-Aknin S. (2018) Immunopathogenesis of Myasthenia Gravis. In: Kaminski H., Kusner L. (eds) Myasthenia Gravis and Related Disorders. Current Clinical Neurology. Humana Press, Cham
  • Phillips, W. D., & Vincent, A. (2016). Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Research5, F1000 Faculty Rev-1513. doi:10.12688/f1000research.8206.1
  • Wolfe, G. I., Kaminski, H. J., Aban, I. B., Minisman, G., Kuo, H. C., Marx, A., … & Heckmann, J. M. (2019). Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial. The Lancet Neurology18(3), 259-268.
  • Zhang, B., Shen, C., Bealmear, B., Ragheb, S., Xiong, W. C., Lewis, R. A., … Mei, L. (2014). Autoantibodies to agrin in myasthenia gravis patients. PloS one9(3), e91816. doi:10.1371/journal.pone.0091816
  • Barohn, R. J., Herbelin, L., & Evaluator, C. (n.d). The Quantitative Myasthenia Gravis  (QMG) Test The Manual.

Supplemental Material

Figure 4: QMG score analysis based on the following test questions that helps determine the pathology and severity of a patient’s disease provided by Barohn, et al.

 

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