Linda Remijn Nelissen

The aim of this thesis was to provide an overview of the therapeutic landscape for patients with myasthenia gravis (MG), with Part I focusing on existing and emerging symptomatic treatment strategies, and Part II on immunomodulatory therapies and their current use in clinical practice. Part I: Symptomatic treatment Chapter 2 presents an extensive literature review on symptomatic therapies for MG. These therapies target the neuromuscular junction directly, although for certain drugs like sympathomimetics, their precise mode of action remains unclear. Three main groups of currently available therapies are described; acetylcholinesterase inhibitors, potassium channel blockers, and sympathomimetic agents. Acetylcholinesterase inhibitors like pyridostigmine and ambenonium chloride, enhance cholinergic transmission by inhibiting the breakdown of acetylcholine in the synaptic cleft. According to national and international guidelines, pyridostigmine is widely accepted as the cornerstone of symptomatic treatment for MG. This is based on observational studies, the earliest of which date back to the mid-1930s, as well as decades of clinical experience. However, no randomized clinical trial has quantified its effect size, and systematic evaluation of its side effect burden is lacking. As a result, it remains challenging to position pyridostigmine relative to other symptomatic therapies. The role of short-acting potassium channel blockers (e.g., amifampridine), which enhance acetylcholine release by prolonging the presynaptic action potential, as well as sympathomimetic agents (e.g., ephedrine, salbutamol, terbutaline), remains unclear due to a lack of robust comparative studies. In addition to currently available treatments, three experimental compounds are discussed: CLC-1 chloride channel inhibitors, fast-skeletal muscle troponin activators, and antisense oligodeoxynucleotides. The latter two are no longer under active development, limiting their future clinical applicability. CLC-1 chloride channel inhibitors appear to be promising with potentially fewer side effects than the current standard. Hopefully, phase III trials will provide greater insight into their efficacy and help clarify their role in the symptomatic treatment of MG patients. In chapter 3 we characterized the effectiveness and side effects of pyridostigmine in a cross-sectional study. Data were collected from 410 out of 642 invited patients participating in the Dutch-Belgian myasthenia patient registry. In a dynamic, for this study developed questionnaire, effectiveness, side effects and net benefit were evaluated. Almost all patients reported to have used pyridostigmine at some point during the course of their disease, with approximately two thirds (62%) continuing its use. The reported net benefit and effectiveness were moderate with frequently reported side effects. Out of all patients currently using pyridostigmine, 91% reported at least one side effect compared to 54% in the control group. The most frequently reported side effects included gastro-intestinal symptoms (flatulence, diarrhea, and abdominal cramps), urinary urgency, muscle cramps, blurred vision, hyperhidrosis, increased salivation, light-headedness and flu-like symptoms. Side effects were cited as the primary reason for discontinuation by 26% of respondents. Factors associated with discontinuation of pyridostigmine were male sex and the presence of MuSK antibodies. In chapter 4 and chapter 5 we describe the results of IMPACT-MG, a randomized double-blinded, placebo controlled crossover trial that evaluated the efficacy and cost-effectiveness of pyridostigmine (part one), followed by a second randomization to assess the efficacy and safety of amifampridine in combination with pyridostigmine (part two) in patients with AChR MG. The findings of part one of IMPACT-MG are described in chapter 4. Nineteen participants were assigned to two five-day treatment periods separated by a two-day washout. Participants received pyridostigmine followed by placebo, or vice versa. All participants had been using pyridostigmine chronically before enrollment, and their trial dose was identical to their usual pre-study dose. The primary endpoint was the within-patient difference in MGII score, a validated score measuring MG disease severity, during pyridostigmine use compared to placebo. Secondary outcome measures included the MG-ADL and QMG, evaluating efficacy; the MG-QoL15r, evaluating quality of life; and the TSQM-9, evaluating treatment satisfaction. Adverse events were systematically recorded, and an economic evaluation was performed from both societal and healthcare perspectives. Treatment with pyridostigmine improved the MGII score by -5.3 points compared with placebo. All secondary endpoints also favored pyridostigmine (QMG -1.4 points, MG-ADL -1.2 points, MG-QoL15r -2 points, and TSQM-9 7.2 points). Adverse events occurred more frequently during pyridostigmine use than during placebo, with fatigue and flatulence being the most commonly reported events. In the cost-utility analysis, pyridostigmine treatment showed lower annual healthcare and societal costs, and annual improved QALYs, compared to treatment without pyridostigmine. In addition, the probability of cost-effectiveness at a willingness-to-pay threshold of €20,000 per QALY was high (>99%), from both societal and healthcare perspectives. Chapter 5 presents the findings from the second part of IMPACT-MG, which evaluated the addition of amifampridine to treatment with pyridostigmine. Amifampridine is a presynaptic potassium channel blocker that prolongs the action potential and thereby enhances acetylcholine release in the synaptic cleft. It is primarily used in patients with Lambert-Eaton myasthenic syndrome and congenital myasthenic syndrome, while its use in AChR MG has been hypothesized but has not previously been studied in randomized controlled trials. To be eligible for participation in part two, patients had either completed part one of the study or failed to complete the two‑day washout period prior to randomization in part. A total of twenty patients were randomized to one of three treatment sequences, each consisting of three treatment periods of five days, separated by a two‑day washout period. During these periods, patients received either 30 mg amifampridine, 60 mg amifampridine, or placebo. The primary and secondary efficacy and safety outcomes were identical to those used in part one. An additional pharmacokinetic/pharmacodynamic (PK/PD) substudy was conducted to assess PK parameters and evaluate potential dose-response relationships. For the primary outcome, measured by the MGII score, the mean treatment difference compared with placebo was -1 point for amifampridine 30 mg and -1.7 points for amifampridine 60 mg. Similar to the primary outcome, no statistically significant differences were observed across any of the secondary efficacy endpoints. In contrast, adverse events occurred more frequently during treatment with amifampridine. The most commonly reported events included paresthesia, fatigue, numbness, dizziness, and sleep disturbances. In three cases, treatment-emergent adverse events were severe enough to necessitate discontinuation of amifampridine. Within the PK/PD substudy, no associations were found between mean steady-state AUCτ, and Cmax and the primary outcome measure. Part II: Immunomodulatory therapies In chapter 6, we provide an overview of current treatment patterns in the Netherlands across different subgroups of MG patients throughout the disease course. We analyzed longitudinal data from adult patients enrolled in the Dutch-Belgian Myasthenia Registry, stratifying them by age at disease onset (≤50 years as early-onset MG [EOMG], and >50 years as late-onset MG [LOMG]) and antibody status (AChR, MuSK, and seronegative). Within the first year after diagnosis, the majority patients initiated pyridostigmine (93%), and after five years, approximately two-thirds continued its use. Furthermore, this study demonstrates that a substantial proportion of patients remains dependent on corticosteroids ten years after disease onset (30-40%). In addition, about one third of patients reported the use of intravenous immunoglobulin therapy at some point during the course of the disease, and 16% of patient reported treatment with plasma exchange. In chapter 7 we describe our clinical experience with sixteen patients with refractory MG treated with efgartigimod, an FcRn blocker, in a retrospective cohort study. A favorable outcome was defined as either a clinically meaningful improvement on at least two outcome measures (MG-ADL, QMG, or MGC) or discontinuation of prednisolone, a prednisolone dose reduction of >10 mg per day, or discontinuation of chronic plasma exchange or IVIg, without the use of rescue medication. A favorable outcome was observed in 56% of patients at the last assessment. Moreover, in 80% of patients, MG-related treatments (prednisolone, azathioprine, plasma exchange, and IVIg) were reduced compared with treatment prior to efgartigimod. All patients had discontinued the treatment regimen as used in the pivotal ADAPT-trial (one infusion per week for four weeks, followed by a variable interval before the next treatment cycle) to administration intervals of 1, 2, or 3 weeks.