Abstract
Background and objectives: Pyridostigmine, an acetylcholinesterase inhibitor, is a symptomatic drug approved for the treatment of myasthenia gravis (MG), but no randomized controlled trials substantiate its widespread use. We aimed to assess the efficacy and cost utility of pyridostigmine in patients with anti-acetylcholine receptor-positive MG (AChR MG).
Methods: A randomized, double-blind, placebo-controlled crossover trial was conducted at Leiden University Medical Center, a tertiary center for the treatment of MG in the Netherlands. Main eligibility criteria were current use of pyridostigmine and a stable dose of other MG treatments. Participants were assigned to a sequence of 2 treatment periods for 5 days separated by a 2-day washout, in which patients either first received placebo and then pyridostigmine, or vice versa. Pyridostigmine dosing matched each participant's prestudy regimen. The primary outcome was change in the Myasthenia Gravis Impairment Index (MGII) score. Secondary efficacy outcome measures included the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale, the Quantitative Myasthenia Gravis (QMG) score, and the revised 15-item Myasthenia Gravis Quality of Life (MG-QOL15r) questionnaire. For the post hoc cost-utility analysis, a mathematical model was developed to translate the observed study results into long-term annual effect on societal costs and quality-adjusted life years (QALYs).
Results: A total of 19 patients (median age 59 years, 58% female) were recruited between March 23, 2023, and February 21, 2024. The estimated mean difference in the MGII score between pyridostigmine and placebo interventions was 5.3 (95% CI 1.9-8.7, p = 0.004). Secondary efficacy outcome measures showed estimated mean differences of 1.4 (95% CI 0.5-2.3) for the QMG score, 1.2 (95% CI 0.5-1.8) for the MG-ADL score, and 2.0 (95% CI 0.03-3.91) for the MG-QoL15r score. The post hoc cost-utility analysis showed lower annual societal costs (€6,565, 95% CI €328-€15,945) and annual improved QALYs (0.106, 95% CI 0.019-0.210) for patients using pyridostigmine.
Discussion: This trial showed that, in patients with AChR MG chronically treated with pyridostigmine, pyridostigmine demonstrated benefit over placebo across all efficacy outcome measures and substantially reduced societal costs.
Trial registration information: The trial was registered at EudraCT (2021-004110-20, registration date: July 12, 2022) and ClinicalTrials.gov (NCT05919407, registration date: June 16, 2023). First patient enrolled: March 23, 2023.
Classification of evidence: This study provides Class I evidence that, in adults with AChR ab-positive ocular or generalized MG on stable standard-of-care therapy and currently using pyridostigmine, pyridostigmine improves MG symptoms compared with placebo.
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Experts Weigh In
Ricardo Roda, MD, PhD, assistant professor of neurology and director of the Myasthenia Gravis Center at Johns Hopkins Medicine, said the complementary scales strengthened the study's design.
“Even if the results were mixed, that kind of thoughtful measurement framework gives clinicians a much more reliable picture of what the drug is actually doing,” he said.
Other leading MG clinicians also thought the study was useful.
“Even after decades of use, having structured, quantifiable evidence like this helps establish a clear benchmark for clinicians and future therapies,” said A. Gordon Smith, MD, FAAN, professor of neurology and endowed distinguished chair in clinical and translational research at Virginia Commonwealth University.
The trial's results align closely with the limited data available for other symptomatic agents in MG. Small randomized studies of Beta2-adrenergic agonists such as terbutaline, as well as ephedrine and investigational chloride channel (ClC-1) inhibitors, have reported QMG improvements in the range of 1 to 3 points.
“While these trials demonstrate consistent statistical significance, the improvements in efficacy outcome scores with all symptomatic therapies remain modest,” Dr. Remijn-Nelissen said. “It is noteworthy that these changes appear to be comparable across different agents.”
Reinforcing Dose Optimization
The study also provided updated data on tolerability. Side effects were reported in 63 percent of patients receiving pyridostigmine compared with 37 percent of those in the placebo group. In the cross-sectional cohort, 91 percent of patients reported side effects during treatment with pyridostigmine, compared with 54 percent of the control group.
Most adverse events were mild to moderate and consistent with cholinergic effects, including gastrointestinal symptoms, such as flatulence and diarrhea; increased secretions; muscle-related complaints; and fatigue. No serious or unexpected adverse events emerged, and the overall safety profile aligned with longstanding clinical experience.
“We've always appreciated that pyridostigmine has gastrointestinal side effects, but much of that understanding has been based on clinical impression rather than rigorous data,” Dr. Kaminksi said. “This study allows us to move beyond anecdote and actually quantify the side effect profile in a meaningful, evidence-based way.”
The frequency of adverse effects, typically cholinergic in nature, underscores the importance of careful dose titration. Although it is already common practice to titrate the dose of pyridostigmine based on clinical effect and side effects, and to taper the medication once symptoms are stable, reporting the high frequency of side effects may further increase clinicians' awareness of the importance of using the lowest effective dose of pyridostigmine and discontinuing it when patients are clinically stable.
Cost-Effective in Modern Care
Beyond clinical endpoints, the study incorporated a post-hoc cost-utility analysis, using modeling to estimate long-term societal impact. The researchers found that use of pyridostigmine was associated with an estimated annual cost savings of approximately 6,565 Euros, or about $7,000, per patient and a gain of 0.106 quality-adjusted life years (QALYs). The projected savings were largely driven by improved functional status, which may reduce health care use and productivity losses.
“Although the magnitude of the effect was relatively modest, pyridostigmine nevertheless demonstrated clear cost-effectiveness, which will likely contribute to its continued role as an important component of the treatment of MG,” Dr. Remijn-Nelissen said.
The results suggest that pyridostigmine use is associated with gains in QALYs and reduced overall costs—findings that could be relevant in health policy discussions, particularly as newer, high-cost biologics and targeted therapies reshape the MG treatment landscape.
“The inclusion of economic and societal metrics is a real strength; it's valuable to understand not just how well the drug works but also how it affects patients' lives on a broader scale,” Dr. Smith said.
Dr. Roda echoed that perspective, noting the findings were somewhat unexpected.
“What surprised me most was seeing a clear economic signal from such a simple, inexpensive drug,” he said. “We tend to think of cost-effectiveness in the context of newer, high-cost therapies, but this shows that even a symptomatic treatment like pyridostigmine can deliver measurable value.”
He pointed out that “what the cost-utility analysis captures is something we don't always measure well in clinic—how patients actually function and feel day to day. Even modest symptomatic improvements can translate into meaningful gains, and that's important because it gives us a benchmark for evaluating the value of the next generation of often much more expensive treatments.”
Reassuring Data—With Caveats
For neurologists, the IMPACT-MG trial offers both validation and recalibration. It confirms that pyridostigmine does, in fact, provide symptomatic benefit, something long assumed but never rigorously proven. At the same time, it tempers expectations about the magnitude of that benefit at the population level.
“This was never intended to change how we treat patients overnight; it was meant to be foundational: to finally validate a therapy we've relied on for decades, to quantify its benefits and risks, and to create a more rigorous framework for future research,” Dr. Kaminski said. “In that sense, the real value isn't that the results were surprising but that we've finally put structure and numbers around what clinicians have long understood from experience.”
Perhaps most importantly, the study highlights a methodological gap: the lack of validated thresholds for clinically meaningful change in trials of symptomatic therapies.
“That represents one of the key insights gained from this trial,” said Dr. Remijn-Nelissen, suggesting that future studies may need to redefine how efficacy is measured in this context. “However, until additional studies are conducted, pyridostigmine's role in MG management remains well established, backed not only by decades of clinical experience but also by this new randomized trial evidence.”
In terms of future studies, Dr. Remijn-Nelissen said that an ideal clinical trial would be conducted to evaluate the effect of pyridostigmine in patients who have never previously used the drug.
“However, due to feasibility concerns, we deliberately chose not to pursue this approach in our study, as recruiting a sufficient number of patients would likely have required a multicenter, and potentially even multinational, study,” he said.
https://neurologytoday.aan.com/doi/10.1097/01.wnt.0001197708.37587.e7
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