Ruiter Annabel M, van Meijgaarden Krista E, Joosten Simone A, Spitali Pietro, Huijbers Maartje G, van Zwet Erik W, Badrising Umesh A, Tannemaat Martijn, Verschuuren Jan J
Department of Neurology, Leiden University Medical Center, the Netherlands.
Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, the Netherlands.
Neurol Neuroimmunol Neuroinflamm. 2025 Nov;12(6):e200468. doi: 10.1212/NXI.0000000000200468. Epub 2025 Sep 18.
Most patients with myasthenia gravis (MG) suffer from fatigue, which can be defined as a subjective lack of energy and difficulty in initiating or sustaining voluntary activities. This is conceptually different from muscle weakness or muscle fatigability. Fatigue is one of the most reported symptoms in MG and has been hypothesized to be an innate mechanism to minimize muscle activity in order to protect muscles from (further) damage. The exact pathophysiology of fatigue remains unclear, and it is very likely a multifactorial phenomenon. The aim of this study was to provide a better understanding on the pathophysiology of fatigue in MG.
We analyzed 38 serum biomarkers including various cytokines and myokines in a cohort of 116 anti-acetylcholine receptor-positive patients with MG. A multivariate linear regression analysis for each biomarker was performed in search for a correlation with fatigue. The following preselected covariates were included in the primary analysis: sex, age, disease severity, depression and anxiety scores, nonsteroid immune suppressive medication, and cumulative prednisone dosage in the past 6 months.
Severe fatigue was present in 64% of patients. Results show a robust correlation between fatigue and C-reactive protein (CRP) in the primary analysis. This correlation persisted when additionally adjusting for BMI, strenuous physical activities, and hemoglobulin levels.
Our findings suggest that chronic low-grade inflammation, mediated by CRP, contributes to the pathogenesis of fatigue in MG. This aligns with the hypothesis that local peripheral inflammatory processes induce systemic inflammatory cascades responsible for fatigue.
大多数重症肌无力（MG）患者会出现疲劳症状，疲劳可定义为主观上缺乏能量以及开始或维持自主活动存在困难。这在概念上与肌肉无力或肌肉易疲劳性不同。疲劳是MG中报告最多的症状之一，据推测是一种内在机制，可尽量减少肌肉活动，以保护肌肉免受（进一步）损伤。疲劳的确切病理生理学仍不清楚，很可能是一种多因素现象。本研究的目的是更好地理解MG中疲劳的病理生理学。
我们分析了116例抗乙酰胆碱受体阳性MG患者队列中的38种血清生物标志物，包括各种细胞因子和肌肉因子。对每种生物标志物进行多变量线性回归分析，以寻找与疲劳的相关性。主要分析中纳入了以下预先选定的协变量：性别、年龄、疾病严重程度、抑郁和焦虑评分、非甾体免疫抑制药物以及过去6个月内泼尼松的累积剂量。
64%的患者存在严重疲劳。主要分析结果显示疲劳与C反应蛋白（CRP）之间存在显著相关性。在进一步调整体重指数、剧烈体育活动和血红蛋白水平后，这种相关性仍然存在。
我们的研究结果表明，由CRP介导的慢性低度炎症促成了MG中疲劳的发病机制。这与局部外周炎症过程引发导致疲劳的全身炎症级联反应的假说相符。
