Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia

Abstract

Myalgic encephalomyelitis (ME) and fibromyalgia (FM) are overlapping syndromes characterized by persistent fatigue, cognitive difficulties, and post-exertional malaise (PEM), yet they lack objective biomarkers for diagnosis and treatment. Fibroblast growth factor 21 (FGF-21), a stress-responsive metabolic hormone, may offer a promising avenue to distinguish subtypes within these patient populations. In this cross-sectional study, plasma FGF-21 levels were measured in 250 patients (FM = 47; ME = 99; ME + FM = 104) and 54 healthy controls. Participants were categorized based on FGF-21 levels into three groups: low (0-50 pg/mL), normal (51-200 pg/mL), and high (>200 pg/mL). Symptoms burden and cognitive function were assessed using validated questionnaires (SF-36, MFI-20, DSQ, DPEMQ) and the BrainCheck platform. A standardized mechanical provocation maneuver was used to induce PEM. Results showed that elevated FGF-21 levels were frequently observed in ME and ME + FM but varied widely across all groups. Stratification by circulating FGF-21 levels, rather than diagnosis alone, revealed distinct symptom and cognitive profiles. Low FGF-21 levels were linked to worsened PEM perception in FM, increased PEM severity and immune/autonomic symptoms in ME, and poorer mental health in ME + FM. Conversely, high FGF-21 levels correlated with better cognition in ME but greater fatigue in ME + FM. These findings suggest that FGF-21 may serve as a valuable biomarker for identifying clinically meaningful subtypes within ME and FM, supporting the development of personalized treatments. Furthermore, discrepancies between DSQ and DPEMQ highlight the need for objective PEM assessment tools. Overall, FGF-21 shows potential as a biomarker to guide precision medicine in these complex conditions.

Keywords: FGF-21; biomarkers; cognition; fibromyalgia; myalgic encephalomyelitis; symptoms.

Figure 1

Comparison of health-related questionnaire scores across study groups. Box plots illustrating the distribution of scores for the 36-Item Short Form Survey (SF-36), the Multidimensional Fatigue Inventory (MFI-20), and the DePaul Symptom Questionnaire (DSQ) across the fibromyalgia (FM, n = 47), myalgic encephalomyelitis (ME, n = 99), myalgic encephalomyelitis with fibromyalgia (ME + FM, n = 104), and healthy control (HC, n = 54) cohorts. (a) For the SF-36, higher scores indicate better-perceived health, whereas higher scores indicate greater symptom severity for MFI-20 (b) and DSQ (c). Each box plot represents the distribution of scores, with the embedded box plot showing the median (central line), interquartile range (box edges), and 1.5× interquartile range (whiskers). Individual data points are overlaid as dots. Statistical significance between groups was assessed using ANOVA followed by Tukey’s post hoc test. **** p < 0.0001 for all comparisons between disease groups and HC groups.

Figure 2

Circulating FGF-21 levels in patient groups and the impact of biological sex. (a) FGF-21 levels are evaluated by diagnostic group. Box plots show FGF-21 concentrations (pg/mL) on the y-axis for patients with fibromyalgia (FM, blue, n = 47), myalgic encephalomyelitis (ME, red, n = 99), myalgic encephalomyelitis with fibromyalgia (ME + FM, green, n = 104), and healthy controls (HC, purple, n = 54). Compared to healthy controls, higher FGF-21 levels are observed in ME and ME + FM patient groups, though significant heterogeneity exists within all cohorts. (b) FGF-21 levels are evaluated by biological sex. The data with females (F, red) and males (M, blue) show no statistically significant differences in FGF-21 levels among the patient subgroups (FM, ME, ME + FM) or within the healthy control group. For both panels, each box plot represents the probability density of the data, with the embedded box plot indicating the median (central line), interquartile range (box edges), and 1.5× interquartile range (whiskers). Individual data points are overlaid as dots. Statistical significance was assessed using ANOVA followed by Tukey’s post hoc test. * p < 0.05 is considered statistically significant.

Figure 3

Cognitive performance and the impact of FGF-21 stratification across patient phenotypes. (a) Comparison of overall combined BrainCheck cognitive scores (as population percentiles) for fibromyalgia (FM, blue, n = 39), myalgic encephalomyelitis (ME, red, n = 62), and myalgic encephalomyelitis with fibromyalgia (ME + FM, green, n = 56) groups. (b) Comparison of digit symbol substitution scores (assuming higher values denote better performance) across the FM (blue, n = 39), ME (red, n = 62), and ME + FM (green, n = 56) groups. (c) Examination of mental flexibility within the FM group, stratified by FGF-21 levels (pg/mL) (assuming blue = low FGF-21 (n = 6), red = normal FGF-21 (n = 21), green = high FGF-21 (n = 12)). (d) Immediate recognition in ME subgroups based on FGF-21 (assuming blue = low FGF-21 (n = 11), red = normal FGF-21 (n = 33), green = high FGF-21 (n = 18)). Data presented in the box plot represents the probability density of the data, with the embedded box plot indicating the median (central line), interquartile range (box edges), and 1.5× interquartile range (whiskers). Individual data points are overlaid as dots. Statistical significance was assessed using ANOVA followed by Tukey’s post hoc test. * p < 0.05 and ** p < 0.001.