Fibromyalgia

Complex MONDO:0005546 Pathograph 3 Show in embeddings browser Musculoskeletal Disease Neurological Disease

Fibromyalgia is characterized by central sensitization, in which augmented central pain processing with elevated excitatory neurotransmitters amplifies pain perception. Impaired descending inhibition from reduced serotonin and norepinephrine, neuroinflammatory glial activation, HPA-axis dysregulation, and small-fiber pathology compound the heightened pain sensitivity. These mechanisms produce widespread chronic musculoskeletal pain accompanied by fatigue, sleep disturbance, and cognitive symptoms.

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6
Pathophys.
10
Phenotypes
2
Gaps
3
Pathograph
9
Genes
10
Medical Actions
2
Subtypes
7
Datasets
6
References
2
Deep Research
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Subtypes

2
Central Sensitization Predominant
Widespread pain driven primarily by central amplification without demonstrable small-fiber neuropathy. Encompasses approximately 50-60% of patients with normal intraepidermal nerve fiber density on skin biopsy.
Small Fiber Neuropathy Subtype
Approximately 40-55% of FM patients have reduced intraepidermal nerve fiber density on skin biopsy. Peripheral nociceptive input from dysfunctional C- and Aδ-fibers may sustain or amplify central sensitization. Characterized by generalized reduction of skin innervation (proximal and distal) associated with higher symptom severity.
C

Comorbidities

Asthma <-> Fibromyalgia
Disease B UNKNOWN CANDIDATE
Chronic Obstructive Pulmonary Disease <-> Fibromyalgia
Disease B UNKNOWN CANDIDATE
Endometriosis <-> Fibromyalgia
Disease B A_BEFORE_B CANDIDATE
Hypermobile Ehlers-Danlos Syndrome <-> Fibromyalgia
Disease B UNKNOWN CANDIDATE
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Discussions and Knowledge Gaps

2
Does small-fiber peripheral pathology cause central sensitization in fibromyalgia, or does primary central nervous system dysfunction lead to retrograde small-fiber degeneration — and can these be distinguished clinically?
KNOWLEDGE GAP OPEN gap_fm_peripheral_vs_central_causation
Attached to
pathophysiology#Small Fiber Pathology pathophysiology#Central Sensitization pathophysiology#Neuroinflammation
Approximately 50% of FM patients have reduced intraepidermal nerve fiber density, but the causal direction between peripheral small-fiber loss and central sensitization remains unresolved (Sommer & Üçeyler 2025). Three competing models exist: (A) peripheral-to-central, where tonic nociceptive input from damaged C-fibers drives central sensitization via wind-up; (B) central-to-peripheral, where HPA dysregulation and neuroinflammation cause retrograde small-fiber degeneration; and (C) shared upstream cause (immune insult, gut dysbiosis, low-grade inflammation) simultaneously driving both. Resolving this gap determines whether treating small-fiber pathology is disease-modifying or symptomatic, and whether the FM-SFN subtype requires distinct therapeutic targeting.
What are the sex-specific pathophysiological mechanisms that might explain differential fibromyalgia presentation, severity, and prevalence between women and men? Do sex-hormone-regulated immune tolerance, neuroendocrine signaling, pain processing circuits, or other mechanisms contribute to the observed female predominance?
KNOWLEDGE GAP OPEN gap_fm_sex_specific_pathophysiology
Attached to
pathophysiology#HPA Axis Dysregulation pathophysiology#Neuroinflammation pathophysiology#Central Sensitization
A 2026 systematic review (Kaur et al., PMID:42455336) documents that fibromyalgia is reported to be more frequent in women than men (2.4-6.8% in women vs. 0.2-2.4% in men), but notes that "the true sex-specific prevalence remains uncertain and potential underlying mechanisms are unknown." Critically, the review found that men with FMS were examined in only 3.7% of studies, direct sex comparisons were reported in 27.7%, and "no studies have investigated pathophysiological sex differences." The reported female predominance may reflect ascertainment bias, true biological sex differences, or both. Kaur et al. do not propose candidate mechanisms; the three domains below are this entry's own framing of where a sex difference could plausibly arise, offered to scope future work rather than as findings of the cited review: (1) sex-differentiated neuroendocrine/hormonal pathways, such as estrogen and progesterone receptor signaling effects on nociception, immune tolerance, and central sensitization; (2) sex-specific immune dysregulation, such as differential Th17 and regulatory T cell balance; and (3) sex differences in pain processing circuit development and function. None of the three has been tested for a sex difference in fibromyalgia. Resolving this gap is essential for validating the clinical phenotype as universal and informing sex-informed clinical approaches.
Proposed experiments
Sex-balanced mechanistic phenotyping cohort in fibromyalgia
sex-stratified cross-sectional mechanistic cohort study Relation: this experiment is of type this experiment type This experiment is of type sex-stratified cross-sectional mechanistic cohort study.
exp_fm_sex_balanced_mechanistic_cohort
Enroll a deliberately sex-balanced fibromyalgia cohort with matched pain-free controls, recruited against identical diagnostic criteria in both sexes so that ascertainment is not confounded with sex. Profile the three candidate domains in the same participants: neuroendocrine (diurnal cortisol and the HPA response to a standardized stressor, plus sex-hormone panels and, in women, menstrual-cycle or menopausal-status stratification), immune (circulating Th17 and regulatory T cell frequencies and cytokine profiles), and pain processing (quantitative sensory testing with conditioned pain modulation and temporal summation, and skin-biopsy intraepidermal nerve fiber density). The first-order result is whether the diagnostic criteria themselves ascertain men and women differently.
Readouts
Sex difference in HPA axis reactivity
pathophysiology#HPA Axis Dysregulation
Direction: PRESENT ABSENT
Sex difference in inflammatory and T cell profile
pathophysiology#Neuroinflammation
Direction: PRESENT ABSENT
Sex difference in central pain amplification
pathophysiology#Central Sensitization
Direction: PRESENT ABSENT
Controls
Sex-matched pain-free controls
Pain-free men and women matched for age and BMI, so that any observed difference is specific to fibromyalgia rather than a normal sex difference in the same measure.
Decision criterion
The gap resolves toward true biological sex difference if men and women meeting identical criteria diverge on one or more mechanistic readouts beyond the sex difference seen in controls. It resolves toward ascertainment bias if the mechanistic profiles are equivalent once diagnosis is applied symmetrically, implying the female predominance is generated at the point of diagnosis.
Show evidence (2 references)
PMID:42455336 SUPPORT Human Clinical
"the true sex-specific prevalence remains uncertain and potential underlying mechanisms are unknown"
The systematic review explicitly identifies that FM sex-specific epidemiology and pathophysiology are unresolved knowledge gaps requiring future research.
PMID:42455336 SUPPORT Human Clinical
"no studies have investigated pathophysiological sex differences"
Conclusion of the systematic review confirming the complete absence of mechanistic studies comparing sex-specific FM pathophysiology.
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Pathophysiology

6
Central Sensitization
Augmented pain processing in the central nervous system leads to amplified pain perception. Increased excitatory neurotransmitters (glutamate, substance P) and decreased inhibitory modulation.
Pain Processing GO:0048265 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Pain Processing, annotated with response to pain (GO:0048265). GO:0048265 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:7526868 SUPPORT
"CSF SP levels were 3-fold higher in FMS patients than in normal controls (P < 0.001)"
Elevated substance P in cerebrospinal fluid directly supports central sensitization mechanism with increased excitatory nociceptive signaling.
PMID:21684692 SUPPORT
"Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the conversion of glutamate to GABA and decreased expression or activity of this enzyme could result in an imbalance of excitatory and inhibitory neurotransmission in the ascending and descending pain pathways."
Proposes mechanism for excitatory/inhibitory imbalance underlying central sensitization via altered GAD activity affecting glutamate-GABA balance.
PMID:33494476 SUPPORT
"Fibromyalgia is the most common of the central sensitivity syndromes affecting 2-5% of the adult population in the United States. This pain amplification syndrome has enormous societal impact"
Establishes fibromyalgia as a prototypical central sensitivity syndrome with augmented pain processing.
Descending Pain Modulation Dysfunction
Impaired descending inhibitory pathways that normally dampen pain signals, with altered excitatory/inhibitory (glutamate/GABA) balance in ascending and descending pain pathways. Reduced serotonergic and noradrenergic tone in the descending pathways is the proposed contributor to pain amplification and the rationale for SNRI therapy in fibromyalgia.
Neurotransmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Neurotransmission, annotated with chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:21684692 SUPPORT
"A number of neurotransmitters in the ascending and descending pain pathways have been implicated in FM including glutamate and GABA."
Identifies neurotransmitter dysfunction in descending pain pathways as a key mechanism in fibromyalgia pathophysiology.
PMID:21684692 SUPPORT Model Organism
"GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia."
Animal model evidence supporting the role of impaired inhibitory neurotransmission in pain amplification.
Neuroinflammation
Glial cell activation and elevated inflammatory mediators in the CNS may contribute to central sensitization and symptom persistence.
Microglia CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Microglia, annotated with microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
Downstream
Central Sensitization Glial activation and elevated inflammatory mediators amplify nociceptive signaling in the CNS, contributing to the central sensitization phenotype.
Show evidence (4 references)
PMID:22126705 SUPPORT
"We report elevated cerebrospinal fluid and serum concentrations of interleukin-8, but not interleukin-1beta, in FM patients. This profile is in accordance with FM symptoms being mediated by sympathetic activity rather than dependent on prostaglandin associated mechanisms and supports the..."
Direct evidence of central inflammation in fibromyalgia via elevated CSF IL-8 levels, supporting glial cell activation hypothesis.
PMID:22126705 SUPPORT
"Activation of glia cells resulting in intrathecal elevation of cytokines and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia."
Establishes theoretical framework linking glial activation to intrathecal cytokine elevation in fibromyalgia pathophysiology.
PMID:29684996 SUPPORT
"Mast cells are involved in FM by releasing proinflammatory cytokines, chemokines, chemical mediators, and PGD2. TNF is a cytokine generated by MCs and its level is higher in FM."
Identifies mast cell-mediated inflammation as a contributor to low-grade chronic neuroinflammation in fibromyalgia.
+ 1 more reference
HPA Axis Dysregulation
Blunted cortisol response to stress and altered diurnal cortisol rhythm may contribute to fatigue and pain sensitivity.
Stress Response GO:0006950 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Stress Response, annotated with response to stress (GO:0006950). GO:0006950 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:7980669 SUPPORT
"Patients with FM had low 24-hour urinary free cortisol, but normal peak and elevated trough plasma cortisol levels, compared with normal subjects."
Documents specific HPA axis abnormalities including low urinary cortisol and elevated trough levels supporting HPA dysregulation mechanism.
PMID:15157948 SUPPORT
"There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (P <.01)."
Demonstrates altered circadian cortisol rhythm with delayed decline indicating loss of HPA axis resiliency.
PMID:7980669 SUPPORT
"These data support the view that HPA axis function is perturbed in patients with FM."
Concludes that HPA axis perturbations are a characteristic feature of fibromyalgia pathophysiology.
Small Fiber Pathology
Structural and functional abnormalities of thinly myelinated Aδ and unmyelinated C-fibers affecting approximately 50% of patients (FM-SFN subtype). Reduced intraepidermal nerve fiber density (IENFD) with proximal predominant pattern contributes ongoing peripheral nociceptive input.
Peripheral Sensory Neurons CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Peripheral Sensory Neurons, annotated with sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
Downstream
Central Sensitization Peripheral nociceptive input from dysfunctional C- and Aδ-fibers may sustain or amplify central sensitization via wind-up and long-term potentiation-like synaptic strengthening.
Show evidence (1 reference)
DOI:10.1097/pr9.0000000000001220 SUPPORT
"About 50% of women with fibromyalgia syndrome have reduced skin innervation."
Systematic review documents reduced intraepidermal nerve fiber density in ~50% of FM patients across international cohorts, establishing small fiber pathology as a feature of a major patient subgroup.
Genetic Susceptibility
Multiple genetic variants affect neurotransmitter systems, pain processing, and sensory signaling. CNS-enriched heritability with neural gene prioritization establishes genetic predisposition to altered pain perception and modulation.
Pain Perception GO:0019233 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Pain Perception, annotated with sensory perception of pain (GO:0019233). GO:0019233 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:21905019 SUPPORT
"Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4."
Large-scale genetic study identifies TAAR1, RGS4, CNR1, and GRIA4 as genes with evidence of association with fibromyalgia in replication cohort.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Fibromyalgia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Musculoskeletal 1
Joint Stiffness FREQUENT HP:0001387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint Stiffness (HP:0001387). HP:0001387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29684996 SUPPORT
"FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep."
Identifies joint stiffness as one of the characteristic clinical manifestations of fibromyalgia.
Nervous System 6
Sleep Disturbance VERY_FREQUENT HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep Disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Non-restorative sleep
Show evidence (2 references)
PMID:29684996 SUPPORT
"FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep."
Documents non-restorative sleep as a core feature of fibromyalgia clinical presentation.
PMID:21684692 SUPPORT
"FM is associated with poor sleep, specifically disrupted non-rapid eye movement (NREM) sleep, and the pharmacological induction of NREM sleep is associated with the activation of GAD-containing neurons in the preoptic hypothalamus."
Links sleep disturbance in fibromyalgia to GABAergic neurotransmission dysfunction in sleep-regulating brain regions.
Cognitive Dysfunction FREQUENT Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive Impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Fibro fog
Headaches FREQUENT HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Depression FREQUENT HP:0000716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depression (HP:0000716). HP:0000716 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29684996 SUPPORT
"FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep."
Identifies depression as a characteristic psychiatric comorbidity in fibromyalgia.
PMID:21684692 SUPPORT
"Stress, depression, and anxiety, which are often comorbid with FM, decrease GAD activity."
Links depression in fibromyalgia to decreased GAD enzyme activity affecting neurotransmitter balance.
Anxiety FREQUENT HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21684692 SUPPORT
"Stress, depression, and anxiety, which are often comorbid with FM, decrease GAD activity."
Documents anxiety as a common comorbidity in fibromyalgia associated with altered GABAergic function.
Autonomic Dysfunction FREQUENT Abnormal autonomic nervous system physiology HP:0012332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autonomic Dysfunction, annotated with Abnormal autonomic nervous system physiology (HP:0012332). HP:0012332 is a phenotype from the Human Phenotype Ontology.
Including orthostatic intolerance, temperature dysregulation
Constitutional 3
Chronic Widespread Pain VERY_FREQUENT Chronic pain HP:0012532 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic Pain (HP:0012532). HP:0012532 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:21684692 SUPPORT
"Fibromyalgia (FM) is a condition of chronic generalized musculoskeletal pain that is thought to be a disorder of central pain sensitization."
Defines chronic widespread pain as the cardinal feature of fibromyalgia and links it to central sensitization mechanism.
PMID:21684692 SUPPORT Other
"The defining symptom of FM is pain"
Identifies pain as the defining symptom of fibromyalgia. Split from the adjoining mouse clause so this item carries a single evidence_source.
PMID:21684692 SUPPORT Model Organism
"GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia."
Animal-model evidence that impaired GABAergic inhibition produces hyperalgesia, offered as a mechanism for the human pain phenotype rather than as direct human evidence.
Fatigue VERY_FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29684996 SUPPORT
"FM is characterized by chronic widespread pain, fatigue, aching, joint stiffness, depression, cognitive dysfunction and non-restorative sleep."
Identifies fatigue as one of the core clinical manifestations of fibromyalgia alongside pain and other symptoms.
Hypersensitivity to Touch FREQUENT Allodynia HP:0012533 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Allodynia (HP:0012533). HP:0012533 is a phenotype from the Human Phenotype Ontology.
Allodynia and hyperalgesia
🧬

Genetic Associations

9
COMT (Risk Factor)
Gene: COMT hgnc:2228 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COMT (hgnc:2228). hgnc:2228 is a gene from the HUGO Gene Nomenclature Committee.
SLC6A4 (Risk Factor)
Gene: SLC6A4 hgnc:11050 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC6A4 (hgnc:11050). hgnc:11050 is a gene from the HUGO Gene Nomenclature Committee.
HTR2A (Risk Factor)
Gene: HTR2A hgnc:5293 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HTR2A (hgnc:5293). hgnc:5293 is a gene from the HUGO Gene Nomenclature Committee.
TAAR1 (Risk Factor)
Gene: TAAR1 hgnc:17734 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TAAR1 (hgnc:17734). hgnc:17734 is a gene from the HUGO Gene Nomenclature Committee.
RGS4 (Risk Factor)
Gene: RGS4 hgnc:10000 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RGS4 (hgnc:10000). hgnc:10000 is a gene from the HUGO Gene Nomenclature Committee.
CNR1 (Risk Factor)
Gene: CNR1 hgnc:2159 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CNR1 (hgnc:2159). hgnc:2159 is a gene from the HUGO Gene Nomenclature Committee.
GRIA4 (Risk Factor)
Gene: GRIA4 hgnc:4574 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GRIA4 (hgnc:4574). hgnc:4574 is a gene from the HUGO Gene Nomenclature Committee.
TRPV2 (Protective Factor)
Gene: TRPV2 hgnc:18082 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRPV2 (hgnc:18082). hgnc:18082 is a gene from the HUGO Gene Nomenclature Committee.
TRPV3 (Risk Factor)
Gene: TRPV3 hgnc:18084 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRPV3 (hgnc:18084). hgnc:18084 is a gene from the HUGO Gene Nomenclature Committee.
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Medical Actions

10
Duloxetine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: duloxetine CHEBI:36796 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses duloxetine (CHEBI:36796). CHEBI:36796 is a therapeutic agent from Chemical Entities of Biological Interest.
SNRI, FDA-approved for fibromyalgia. Modulates serotonin and norepinephrine for pain relief.
Milnacipran
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: milnacipran CHEBI:135005 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses milnacipran (CHEBI:135005). CHEBI:135005 is a therapeutic agent from Chemical Entities of Biological Interest.
SNRI, FDA-approved for fibromyalgia. Dual neurotransmitter modulation.
Pregabalin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pregabalin CHEBI:64356 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pregabalin (CHEBI:64356). CHEBI:64356 is a therapeutic agent from Chemical Entities of Biological Interest.
Alpha-2-delta ligand, FDA-approved for fibromyalgia. Reduces abnormal neural excitability.
Gabapentin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: gabapentin CHEBI:42797 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses gabapentin (CHEBI:42797). CHEBI:42797 is a therapeutic agent from Chemical Entities of Biological Interest.
Alpha-2-delta ligand, used off-label for neuropathic pain component.
Amitriptyline
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: amitriptyline CHEBI:2666 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses amitriptyline (CHEBI:2666). CHEBI:2666 is a therapeutic agent from Chemical Entities of Biological Interest.
Low-dose tricyclic antidepressant for pain modulation and sleep improvement.
Aerobic Exercise
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Structured physical activity with strong evidence for pain reduction and functional improvement.
Cognitive Behavioral Therapy
Action: psychotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is psychotherapy, annotated with Behavioral Counseling (NCIT:C181743). NCIT:C181743 is a clinical intervention from the NCI Thesaurus. Ontology label: Behavioral Counseling NCIT:C181743
Platform: Behavioral / lifestyle
Psychological intervention addressing pain catastrophizing, coping strategies, and behavioral modification.
Sleep Hygiene Education
Action: patient educationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is patient education, annotated with Behavioral Counseling (NCIT:C181743). NCIT:C181743 is a clinical intervention from the NCI Thesaurus. Ontology label: Behavioral Counseling NCIT:C181743
Platform: Behavioral / lifestyle
Behavioral interventions to improve sleep quality and reduce non-restorative sleep patterns.
Mindfulness-Based Stress Reduction
Action: behavioral interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is behavioral intervention (NCIT:C15184). NCIT:C15184 is a clinical intervention from the NCI Thesaurus. Ontology label: Behavioral Intervention NCIT:C15184
Meditation and mindfulness practices for pain management and stress reduction.
Aquatic Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Water-based exercise therapy for low-impact conditioning and pain relief.
🌍

Environmental Factors

4
Physical Trauma
Can trigger onset
Show evidence (1 reference)
PMID:29428291 SUPPORT Human Clinical
"the majority of studies described a significant association between prior physically traumatic events and the onset of chronic widespread pain or fibromyalgia"
Systematic review finds a significant association between prior physical trauma and fibromyalgia onset across the majority of included studies.
Psychological Stress
psychological stress XCO:0001265 Experimental Conditions Ontology (XCO) Relation: this environmental factor is this exposure This environmental factor is psychological stress, annotated with stress (XCO:0001265). XCO:0001265 is an exposure from the Experimental Conditions Ontology.
Common precipitant
Show evidence (1 reference)
PMID:29428291 SUPPORT Human Clinical
"Elevated rates of psychological trauma in fibromyalgia patients were demonstrated across the literature and several studies indicate a mediating effect of post-traumatic stress disorder"
Same systematic review reports elevated rates of psychological trauma preceding fibromyalgia, with PTSD as a mediating factor.
Infections
Infectious agent exposure ECTO:3000000 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is Infectious agent exposure, annotated with exposure to organism (ECTO:3000000). ECTO:3000000 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
May trigger in susceptible individuals. Bound to ECTO:3000000 (exposure to organism) rather than the previous XCO:0000236, a cross-ontology move that also broadens pathogen to any organism. ECTO has no generic pathogen- or infectious-agent-exposure term, so the broadening is the deliberate "no term beats a bad one" tradeoff and not an error to be reverted; the pathogen sense is carried by preferred_term.
Show evidence (1 reference)
PMID:18706528 SUPPORT Human Clinical
"Certain infections including hepatitis C virus, HIV and Lyme disease have been temporally associated with the development of FMS"
Review identifies specific infections temporally associated with fibromyalgia syndrome (FMS) onset.
Sleep Disorders
disturbed sleep XCO:0001068 Experimental Conditions Ontology (XCO) Relation: this environmental factor is this exposure This environmental factor is disturbed sleep, annotated with sleep (XCO:0001068). XCO:0001068 is an exposure from the Experimental Conditions Ontology.
Bidirectional relationship
Show evidence (1 reference)
PMID:39062116 SUPPORT Human Clinical
"healthy individuals experiencing sleep disorders inherently trigger musculoskeletal pain processes"
Review supports the sleep-to-pain direction of the bidirectional relationship between sleep disturbance and fibromyalgia pain.
🔬

Biochemical Markers

3
Substance P (Elevated)
Context: CSF levels increased
Show evidence (1 reference)
PMID:7526868 SUPPORT
"CSF SP levels were 3-fold higher in FMS patients than in normal controls (P < 0.001)"
Documents dramatic elevation of substance P in cerebrospinal fluid of fibromyalgia patients.
Glutamate (Elevated)
Context: Insula levels on MRS
Show evidence (1 reference)
PMID:21684692 SUPPORT
"Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the conversion of glutamate to GABA and decreased expression or activity of this enzyme could result in an imbalance of excitatory and inhibitory neurotransmission"
Supports mechanism for elevated glutamate through impaired conversion to GABA.
Serotonin (Decreased)
Context: Proposed reduction of serotonergic tone in descending inhibitory pathways, inferred largely from the clinical efficacy of serotonin-norepinephrine reuptake inhibitors (duloxetine, milnacipran) rather than from a directly measured deficit.
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Related Datasets

7
Identification of unique genomic signatures in patients with fibromyalgia and chronic pain geo:GSE221921
Fibromyalgia is a chronic pain syndrome characterized by widespread pain. The pathophysiology of fibromyalgia is not clearly understood and there are no specific biomarkers available for accurate diagnosis. Here we define genomic signatures using high throughput RNA sequencing on 96 fibromyalgia and 93 matched controls. Our findings revealed two major fibromyalgia-associated expression signatures. The first group included 44 patients with a signature enriched for gene expression associated with extracellular matrix and downregulation of RhoGDI signaling pathway.
human BULK RNA SEQ n=189
PMID:38366049
Identified by GEO DataSets index search for Fibromyalgia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity geo:GSE269047
Research of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM), two acquired chronic illnesses affecting mainly females, has failed to ascertain their frequent co-appearance and etiology. Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored.
human MICROARRAY n=43
PMID:40338225
Identified by GEO DataSets index search for Fibromyalgia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Peripheral Blood Gene Expression in Fibromyalgia Patients Reveals Potential Biological Markers and Physiological Pathways geo:GSE67311
Fibromyalgia (FM) is a common pain disorder characterized by dysregulation in the processing of pain. Although FM has similarities with other rheumatologic pain disorders, the search for objective markers has not been successful. In the current study we analyzed gene expression in the whole blood of 70 fibromyalgia patients and 70 healthy matched controls. Global molecular profiling revealed an upregulation of several inflammatory molecules in FM patients and downregulation of specific pathways related to hypersensitivity and allergy. There was a differential expression of genes in known pathways for pain processing, such as glutamine/glutamate signaling and axonal development.
human MICROARRAY n=142
PMID:27157394
Identified by GEO DataSets index search for Fibromyalgia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Exome sequencing of Fibromyalgia patients ega:EGAS00001003825
Fibromyalgia is a complex disorder characterized by increased sensitivity to pain and extreme tiredness. It affects mostly women, and its causes are unknown. In this study we have performed exome sequencing of 87 fibromyalgia cases, including some sibling pairs, to perform rare variant association analysis and identify fibromyalgia risk factors. A few of the included samples have been also included in a previous GWAS study.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Fibromyalgia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Exome sequencing of Fibromyalgia patients ega:EGAS00001003826
Fibromyalgia is a complex disorder characterized by increased sensitivity to pain and extreme tiredness. It affects mostly women, and its causes are unknown. In this study we have performed exome sequencing of 87 fibromyalgia cases, including some sibling pairs, to perform rare variant association analysis and identify fibromyalgia risk factors. A few of the included samples have been also included in a previous GWAS study.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Fibromyalgia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Fibromyalgia versus small fiber neuropathy: Diverse keratinocyte transcriptome signature ega:EGAS00001005004
We provide a diverse keratinocyte transcriptome signature between SFN and FMS patients, which may hint towards distinct pathomechanisms of small fiber sensitization and lay the basis for advanced diagnostics in both entities
human
PMID:33675632
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Fibromyalgia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Proteomic Analysis of Cerebrospinal Fluids from Chronic Fatigue Syndrome Patients with and without Co-existing Fibromyalgia massive:MSV000090685
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other. To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other.
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Fibromyalgia"). Retrieved 2026-08-02.
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name: Fibromyalgia
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Fibromyalgia is characterized by central sensitization, in which augmented central pain processing with elevated excitatory neurotransmitters amplifies pain perception.
  Impaired descending inhibition from reduced serotonin and norepinephrine, neuroinflammatory glial activation, HPA-axis dysregulation, and small-fiber pathology compound the heightened pain sensitivity.
  These mechanisms produce widespread chronic musculoskeletal pain accompanied by fatigue, sleep disturbance, and cognitive symptoms.
category: Complex
parents:
- Musculoskeletal Disease
- Neurological Disease
disease_term:
  preferred_term: fibromyalgia
  term:
    id: MONDO:0005546
    label: fibromyalgia
pathophysiology:
- name: Central Sensitization
  description: >
    Augmented pain processing in the central nervous system leads to
    amplified pain perception. Increased excitatory neurotransmitters
    (glutamate, substance P) and decreased inhibitory modulation.
  biological_processes:
  - preferred_term: Pain Processing
    term:
      id: GO:0048265
      label: response to pain
  evidence:
  - reference: PMID:7526868
    reference_title: "Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome."
    supports: SUPPORT
    snippet: "CSF SP levels were 3-fold higher in FMS patients than in normal controls
      (P < 0.001)"
    explanation: Elevated substance P in cerebrospinal fluid directly supports
      central sensitization mechanism with increased excitatory nociceptive
      signaling.
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    snippet: "Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the
      conversion of glutamate to GABA and decreased expression or activity of this
      enzyme could result in an imbalance of excitatory and inhibitory neurotransmission
      in the ascending and descending pain pathways."
    explanation: Proposes mechanism for excitatory/inhibitory imbalance
      underlying central sensitization via altered GAD activity affecting
      glutamate-GABA balance.
  - reference: PMID:33494476
    reference_title: "The Search for Biomarkers in Fibromyalgia."
    supports: SUPPORT
    snippet: "Fibromyalgia is the most common of the central sensitivity syndromes
      affecting 2-5% of the adult population in the United States. This pain amplification
      syndrome has enormous societal impact"
    explanation: Establishes fibromyalgia as a prototypical central sensitivity
      syndrome with augmented pain processing.
- name: Descending Pain Modulation Dysfunction
  description: >
    Impaired descending inhibitory pathways that normally dampen pain signals,
    with altered excitatory/inhibitory (glutamate/GABA) balance in ascending and
    descending pain pathways. Reduced serotonergic and noradrenergic tone in the
    descending pathways is the proposed contributor to pain amplification and the
    rationale for SNRI therapy in fibromyalgia.
  biological_processes:
  - preferred_term: Neurotransmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
  evidence:
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    snippet: "A number of neurotransmitters in the ascending and descending pain pathways
      have been implicated in FM including glutamate and GABA."
    explanation: Identifies neurotransmitter dysfunction in descending pain
      pathways as a key mechanism in fibromyalgia pathophysiology.
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia."
    explanation: Animal model evidence supporting the role of impaired
      inhibitory neurotransmission in pain amplification.
- name: Neuroinflammation
  description: >
    Glial cell activation and elevated inflammatory mediators in the
    CNS may contribute to central sensitization and symptom persistence.
  cell_types:
  - preferred_term: Microglia
    term:
      id: CL:0000129
      label: microglial cell
  evidence:
  - reference: PMID:22126705
    reference_title: "Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels."
    supports: SUPPORT
    snippet: "We report elevated cerebrospinal fluid and serum concentrations of interleukin-8,
      but not interleukin-1beta, in FM patients. This profile is in accordance with
      FM symptoms being mediated by sympathetic activity rather than dependent on
      prostaglandin associated mechanisms and supports the hypothesis of glia cell
      activation in response to pain mechanisms."
    explanation: Direct evidence of central inflammation in fibromyalgia via
      elevated CSF IL-8 levels, supporting glial cell activation hypothesis.
  - reference: PMID:22126705
    reference_title: "Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels."
    supports: SUPPORT
    snippet: "Activation of glia cells resulting in intrathecal elevation of cytokines
      and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia."
    explanation: Establishes theoretical framework linking glial activation to
      intrathecal cytokine elevation in fibromyalgia pathophysiology.
  - reference: PMID:29684996
    reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
    supports: SUPPORT
    snippet: "Mast cells are involved in FM by releasing proinflammatory cytokines,
      chemokines, chemical mediators, and PGD2. TNF is a cytokine generated by MCs
      and its level is higher in FM."
    explanation: Identifies mast cell-mediated inflammation as a contributor to
      low-grade chronic neuroinflammation in fibromyalgia.
  - reference: PMID:39996743
    reference_title: "Fibromyalgia and Inflammation: Unrevealing the Connection."
    supports: SUPPORT
    snippet: "Several studies highlight elevated concentrations of pro-inflammatory
      cytokines, dysregulation of immune responses, and neuroinflammation in
      fibromyalgia patients."
    explanation: >
      2025 review confirms neuroinflammation and immune dysregulation as contributors
      to fibromyalgia pathophysiology, supporting the role of glial activation and
      peripheral/central inflammatory processes in symptom persistence.
  downstream:
  - target: Central Sensitization
    description: >
      Glial activation and elevated inflammatory mediators amplify nociceptive
      signaling in the CNS, contributing to the central sensitization phenotype.
- name: HPA Axis Dysregulation
  description: >
    Blunted cortisol response to stress and altered diurnal cortisol
    rhythm may contribute to fatigue and pain sensitivity.
  biological_processes:
  - preferred_term: Stress Response
    term:
      id: GO:0006950
      label: response to stress
  evidence:
  - reference: PMID:7980669
    reference_title: "Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia."
    supports: SUPPORT
    snippet: "Patients with FM had low 24-hour urinary free cortisol, but normal peak
      and elevated trough plasma cortisol levels, compared with normal subjects."
    explanation: Documents specific HPA axis abnormalities including low urinary
      cortisol and elevated trough levels supporting HPA dysregulation
      mechanism.
  - reference: PMID:15157948
    reference_title: "Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome."
    supports: SUPPORT
    snippet: "There was a significant delay in the rate of decline from acrophase
      to nadir for cortisol levels in patients with FMS (P <.01)."
    explanation: Demonstrates altered circadian cortisol rhythm with delayed
      decline indicating loss of HPA axis resiliency.
  - reference: PMID:7980669
    reference_title: "Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia."
    supports: SUPPORT
    snippet: "These data support the view that HPA axis function is perturbed in patients
      with FM."
    explanation: Concludes that HPA axis perturbations are a characteristic
      feature of fibromyalgia pathophysiology.
- name: Small Fiber Pathology
  description: >
    Structural and functional abnormalities of thinly myelinated Aδ and
    unmyelinated C-fibers affecting approximately 50% of patients (FM-SFN subtype).
    Reduced intraepidermal nerve fiber density (IENFD) with proximal predominant
    pattern contributes ongoing peripheral nociceptive input.
  cell_types:
  - preferred_term: Peripheral Sensory Neurons
    term:
      id: CL:0000101
      label: sensory neuron
  evidence:
  - reference: DOI:10.1097/pr9.0000000000001220
    reference_title: "Small fiber pathology in fibromyalgia syndrome"
    supports: SUPPORT
    snippet: "About 50% of women with fibromyalgia syndrome have reduced skin innervation."
    explanation: >
      Systematic review documents reduced intraepidermal nerve fiber density in ~50%
      of FM patients across international cohorts, establishing small fiber pathology
      as a feature of a major patient subgroup.
  downstream:
  - target: Central Sensitization
    description: >
      Peripheral nociceptive input from dysfunctional C- and Aδ-fibers may sustain
      or amplify central sensitization via wind-up and long-term potentiation-like
      synaptic strengthening.
- name: Genetic Susceptibility
  description: >
    Multiple genetic variants affect neurotransmitter systems, pain processing,
    and sensory signaling. CNS-enriched heritability with neural gene prioritization
    establishes genetic predisposition to altered pain perception and modulation.
  biological_processes:
  - preferred_term: Pain Perception
    term:
      id: GO:0019233
      label: sensory perception of pain
  evidence:
  - reference: PMID:21905019
    reference_title: "Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia."
    supports: SUPPORT
    snippet: "Evidence of association in the replication cohort was observed for TAAR1,
      RGS4, CNR1, and GRIA4."
    explanation: Large-scale genetic study identifies TAAR1, RGS4, CNR1, and
      GRIA4 as genes with evidence of association with fibromyalgia in
      replication cohort.
has_subtypes:
- name: FM-CS
  display_name: Central Sensitization Predominant
  description: >
    Widespread pain driven primarily by central amplification without demonstrable
    small-fiber neuropathy. Encompasses approximately 50-60% of patients with normal
    intraepidermal nerve fiber density on skin biopsy.
- name: FM-SFN
  display_name: Small Fiber Neuropathy Subtype
  description: >
    Approximately 40-55% of FM patients have reduced intraepidermal nerve fiber density
    on skin biopsy. Peripheral nociceptive input from dysfunctional C- and Aδ-fibers
    may sustain or amplify central sensitization. Characterized by generalized reduction
    of skin innervation (proximal and distal) associated with higher symptom severity.
phenotypes:
- name: Chronic Widespread Pain
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Chronic Pain
    term:
      id: HP:0012532
      label: Chronic pain
  evidence:
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    snippet: "Fibromyalgia (FM) is a condition of chronic generalized musculoskeletal
      pain that is thought to be a disorder of central pain sensitization."
    explanation: Defines chronic widespread pain as the cardinal feature of
      fibromyalgia and links it to central sensitization mechanism.
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The defining symptom of FM is pain"
    explanation: Identifies pain as the defining symptom of fibromyalgia. Split from
      the adjoining mouse clause so this item carries a single evidence_source.
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia."
    explanation: Animal-model evidence that impaired GABAergic inhibition produces
      hyperalgesia, offered as a mechanism for the human pain phenotype rather than
      as direct human evidence.
- name: Fatigue
  category: Systemic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:29684996
    reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
    supports: SUPPORT
    snippet: "FM is characterized by chronic widespread pain, fatigue, aching, joint
      stiffness, depression, cognitive dysfunction and non-restorative sleep."
    explanation: Identifies fatigue as one of the core clinical manifestations
      of fibromyalgia alongside pain and other symptoms.
- name: Sleep Disturbance
  category: Neurological
  frequency: VERY_FREQUENT
  notes: Non-restorative sleep
  phenotype_term:
    preferred_term: Sleep Disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:29684996
    reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
    supports: SUPPORT
    snippet: "FM is characterized by chronic widespread pain, fatigue, aching, joint
      stiffness, depression, cognitive dysfunction and non-restorative sleep."
    explanation: Documents non-restorative sleep as a core feature of
      fibromyalgia clinical presentation.
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    snippet: "FM is associated with poor sleep, specifically disrupted non-rapid eye
      movement (NREM) sleep, and the pharmacological induction of NREM sleep is associated
      with the activation of GAD-containing neurons in the preoptic hypothalamus."
    explanation: Links sleep disturbance in fibromyalgia to GABAergic
      neurotransmission dysfunction in sleep-regulating brain regions.
- name: Cognitive Dysfunction
  category: Neurological
  frequency: FREQUENT
  notes: Fibro fog
  phenotype_term:
    preferred_term: Cognitive Impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
- name: Headaches
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
- name: Depression
  category: Psychiatric
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:29684996
    reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
    supports: SUPPORT
    snippet: "FM is characterized by chronic widespread pain, fatigue, aching, joint
      stiffness, depression, cognitive dysfunction and non-restorative sleep."
    explanation: Identifies depression as a characteristic psychiatric
      comorbidity in fibromyalgia.
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    snippet: "Stress, depression, and anxiety, which are often comorbid with FM, decrease
      GAD activity."
    explanation: Links depression in fibromyalgia to decreased GAD enzyme
      activity affecting neurotransmitter balance.
- name: Anxiety
  category: Psychiatric
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    snippet: "Stress, depression, and anxiety, which are often comorbid with FM, decrease
      GAD activity."
    explanation: Documents anxiety as a common comorbidity in fibromyalgia
      associated with altered GABAergic function.
- name: Hypersensitivity to Touch
  category: Neurological
  frequency: FREQUENT
  notes: Allodynia and hyperalgesia
  phenotype_term:
    preferred_term: Allodynia
    term:
      id: HP:0012533
      label: Allodynia
- name: Joint Stiffness
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Joint Stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  evidence:
  - reference: PMID:29684996
    reference_title: "Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37."
    supports: SUPPORT
    snippet: "FM is characterized by chronic widespread pain, fatigue, aching, joint
      stiffness, depression, cognitive dysfunction and non-restorative sleep."
    explanation: Identifies joint stiffness as one of the characteristic
      clinical manifestations of fibromyalgia.
- name: Autonomic Dysfunction
  category: Neurological
  frequency: FREQUENT
  notes: Including orthostatic intolerance, temperature dysregulation
  phenotype_term:
    preferred_term: Autonomic Dysfunction
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
biochemical:
- name: Substance P
  presence: Elevated
  context: CSF levels increased
  evidence:
  - reference: PMID:7526868
    reference_title: "Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome."
    supports: SUPPORT
    snippet: "CSF SP levels were 3-fold higher in FMS patients than in normal controls
      (P < 0.001)"
    explanation: Documents dramatic elevation of substance P in cerebrospinal
      fluid of fibromyalgia patients.
- name: Glutamate
  presence: Elevated
  context: Insula levels on MRS
  evidence:
  - reference: PMID:21684692
    reference_title: "Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain."
    supports: SUPPORT
    snippet: "Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the
      conversion of glutamate to GABA and decreased expression or activity of this
      enzyme could result in an imbalance of excitatory and inhibitory neurotransmission"
    explanation: Supports mechanism for elevated glutamate through impaired
      conversion to GABA.
- name: Serotonin
  presence: Decreased
  context: >-
    Proposed reduction of serotonergic tone in descending inhibitory pathways,
    inferred largely from the clinical efficacy of serotonin-norepinephrine
    reuptake inhibitors (duloxetine, milnacipran) rather than from a directly
    measured deficit.
genetic:
- name: COMT
  gene_term:
    preferred_term: COMT
    term:
      id: hgnc:2228
      label: COMT
  association: Risk Factor
  notes: Catecholamine metabolism
- name: SLC6A4
  gene_term:
    preferred_term: SLC6A4
    term:
      id: hgnc:11050
      label: SLC6A4
  association: Risk Factor
  notes: Serotonin transporter
- name: HTR2A
  gene_term:
    preferred_term: HTR2A
    term:
      id: hgnc:5293
      label: HTR2A
  association: Risk Factor
  notes: Serotonin receptor
- name: TAAR1
  gene_term:
    preferred_term: TAAR1
    term:
      id: hgnc:17734
      label: TAAR1
  association: Risk Factor
  notes: Dopamine availability, pain sensitivity
- name: RGS4
  gene_term:
    preferred_term: RGS4
    term:
      id: hgnc:10000
      label: RGS4
  association: Risk Factor
  notes: Descending pain inhibition
- name: CNR1
  gene_term:
    preferred_term: CNR1
    term:
      id: hgnc:2159
      label: CNR1
  association: Risk Factor
  notes: Cannabinoid receptor CB-1
- name: GRIA4
  gene_term:
    preferred_term: GRIA4
    term:
      id: hgnc:4574
      label: GRIA4
  association: Risk Factor
  notes: Excitatory nociceptive transmission
- name: TRPV2
  gene_term:
    preferred_term: TRPV2
    term:
      id: hgnc:18082
      label: TRPV2
  association: Protective Factor
  notes: TRP channel, protective haplotypes
- name: TRPV3
  gene_term:
    preferred_term: TRPV3
    term:
      id: hgnc:18084
      label: TRPV3
  association: Risk Factor
  notes: TRP channel, contributes to symptoms
environmental:
- name: Physical Trauma
  notes: Can trigger onset
  evidence:
  - reference: PMID:29428291
    reference_title: "A systematic review of precipitating physical and psychological traumatic events in the development of fibromyalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the majority of studies described a significant association between prior physically traumatic events and the onset of chronic widespread pain or fibromyalgia"
    explanation: Systematic review finds a significant association between prior physical trauma and fibromyalgia onset across the majority of included studies.
- name: Psychological Stress
  exposure_term:
    preferred_term: psychological stress
    term:
      id: XCO:0001265
      label: stress
  notes: Common precipitant
  evidence:
  - reference: PMID:29428291
    reference_title: "A systematic review of precipitating physical and psychological traumatic events in the development of fibromyalgia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated rates of psychological trauma in fibromyalgia patients were demonstrated across the literature and several studies indicate a mediating effect of post-traumatic stress disorder"
    explanation: Same systematic review reports elevated rates of psychological trauma preceding fibromyalgia, with PTSD as a mediating factor.
- name: Infections
  exposure_term:
    preferred_term: Infectious agent exposure
    term:
      id: ECTO:3000000
      label: exposure to organism
  notes: >-
    May trigger in susceptible individuals. Bound to ECTO:3000000 (exposure to
    organism) rather than the previous XCO:0000236, a cross-ontology move that
    also broadens pathogen to any organism. ECTO has no generic pathogen- or
    infectious-agent-exposure term, so the broadening is the deliberate "no term
    beats a bad one" tradeoff and not an error to be reverted; the pathogen
    sense is carried by preferred_term.
  evidence:
  - reference: PMID:18706528
    reference_title: "Etiology of fibromyalgia: the possible role of infection and vaccination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Certain infections including hepatitis C virus, HIV and Lyme disease have been temporally associated with the development of FMS"
    explanation: Review identifies specific infections temporally associated with fibromyalgia syndrome (FMS) onset.
- name: Sleep Disorders
  exposure_term:
    preferred_term: disturbed sleep
    term:
      id: XCO:0001068
      label: sleep
  notes: Bidirectional relationship
  evidence:
  - reference: PMID:39062116
    reference_title: "Fibromyalgia: A Review of the Pathophysiological Mechanisms and Multidisciplinary Treatment Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "healthy individuals experiencing sleep disorders inherently trigger musculoskeletal pain processes"
    explanation: Review supports the sleep-to-pain direction of the bidirectional relationship between sleep disturbance and fibromyalgia pain.
treatments:
- name: Duloxetine
  description: SNRI, FDA-approved for fibromyalgia. Modulates serotonin and
    norepinephrine for pain relief.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: duloxetine
      term:
        id: CHEBI:36796
        label: duloxetine
- name: Milnacipran
  description: SNRI, FDA-approved for fibromyalgia. Dual neurotransmitter
    modulation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: milnacipran
      term:
        id: CHEBI:135005
        label: milnacipran
- name: Pregabalin
  description: Alpha-2-delta ligand, FDA-approved for fibromyalgia. Reduces
    abnormal neural excitability.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pregabalin
      term:
        id: CHEBI:64356
        label: pregabalin
- name: Gabapentin
  description: Alpha-2-delta ligand, used off-label for neuropathic pain
    component.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gabapentin
      term:
        id: CHEBI:42797
        label: gabapentin
- name: Amitriptyline
  description: Low-dose tricyclic antidepressant for pain modulation and sleep
    improvement.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amitriptyline
      term:
        id: CHEBI:2666
        label: amitriptyline
- name: Aerobic Exercise
  description: Structured physical activity with strong evidence for pain
    reduction and functional improvement.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Cognitive Behavioral Therapy
  description: Psychological intervention addressing pain catastrophizing,
    coping strategies, and behavioral modification.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: psychotherapy
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
- name: Sleep Hygiene Education
  description: Behavioral interventions to improve sleep quality and reduce
    non-restorative sleep patterns.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: patient education
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
- name: Mindfulness-Based Stress Reduction
  description: Meditation and mindfulness practices for pain management and
    stress reduction.
  treatment_term:
    preferred_term: behavioral intervention
    term:
      id: NCIT:C15184
      label: Behavioral Intervention
- name: Aquatic Therapy
  description: Water-based exercise therapy for low-impact conditioning and pain
    relief.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
discussions:
- discussion_id: gap_fm_peripheral_vs_central_causation
  prompt: >-
    Does small-fiber peripheral pathology cause central sensitization in fibromyalgia,
    or does primary central nervous system dysfunction lead to retrograde small-fiber
    degeneration — and can these be distinguished clinically?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Small Fiber Pathology
  - pathophysiology#Central Sensitization
  - pathophysiology#Neuroinflammation
  rationale: >-
    Approximately 50% of FM patients have reduced intraepidermal nerve fiber density,
    but the causal direction between peripheral small-fiber loss and central sensitization
    remains unresolved (Sommer & Üçeyler 2025). Three competing models exist: (A)
    peripheral-to-central, where tonic nociceptive input from damaged C-fibers drives
    central sensitization via wind-up; (B) central-to-peripheral, where HPA dysregulation
    and neuroinflammation cause retrograde small-fiber degeneration; and (C) shared
    upstream cause (immune insult, gut dysbiosis, low-grade inflammation) simultaneously
    driving both. Resolving this gap determines whether treating small-fiber pathology
    is disease-modifying or symptomatic, and whether the FM-SFN subtype requires
    distinct therapeutic targeting.
- discussion_id: gap_fm_sex_specific_pathophysiology
  prompt: >-
    What are the sex-specific pathophysiological mechanisms that might explain differential
    fibromyalgia presentation, severity, and prevalence between women and men? Do sex-hormone-regulated
    immune tolerance, neuroendocrine signaling, pain processing circuits, or other mechanisms
    contribute to the observed female predominance?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#HPA Axis Dysregulation
  - pathophysiology#Neuroinflammation
  - pathophysiology#Central Sensitization
  rationale: >-
    A 2026 systematic review (Kaur et al., PMID:42455336) documents that fibromyalgia is reported
    to be more frequent in women than men (2.4-6.8% in women vs. 0.2-2.4% in men), but notes that
    "the true sex-specific prevalence remains uncertain and potential underlying mechanisms are unknown."
    Critically, the review found that men with FMS were examined in only 3.7% of studies, direct
    sex comparisons were reported in 27.7%, and "no studies have investigated pathophysiological sex
    differences." The reported female predominance may reflect ascertainment bias, true biological
    sex differences, or both. Kaur et al. do not propose candidate mechanisms; the three domains
    below are this entry's own framing of where a sex difference could plausibly arise, offered to
    scope future work rather than as findings of the cited review: (1) sex-differentiated
    neuroendocrine/hormonal pathways, such as estrogen and progesterone receptor signaling effects
    on nociception, immune tolerance, and central sensitization; (2) sex-specific immune dysregulation,
    such as differential Th17 and regulatory T cell balance; and (3) sex differences in pain processing
    circuit development and function. None of the three has been tested for a sex difference in
    fibromyalgia. Resolving this gap is essential for validating the clinical phenotype as universal
    and informing sex-informed clinical approaches.
  evidence:
  - reference: PMID:42455336
    reference_title: "[Fibromyalgia syndrome-Is the designation as a disorder of women a misinterpretation?]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the true sex-specific prevalence remains uncertain and potential underlying mechanisms are unknown"
    explanation: >-
      The systematic review explicitly identifies that FM sex-specific epidemiology and
      pathophysiology are unresolved knowledge gaps requiring future research.
  - reference: PMID:42455336
    reference_title: "[Fibromyalgia syndrome-Is the designation as a disorder of women a misinterpretation?]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "no studies have investigated pathophysiological sex differences"
    explanation: >-
      Conclusion of the systematic review confirming the complete absence of mechanistic
      studies comparing sex-specific FM pathophysiology.
  proposed_experiments:
  - experiment_id: exp_fm_sex_balanced_mechanistic_cohort
    name: Sex-balanced mechanistic phenotyping cohort in fibromyalgia
    description: >-
      Enroll a deliberately sex-balanced fibromyalgia cohort with matched pain-free
      controls, recruited against identical diagnostic criteria in both sexes so that
      ascertainment is not confounded with sex. Profile the three candidate domains in
      the same participants: neuroendocrine (diurnal cortisol and the HPA response to a
      standardized stressor, plus sex-hormone panels and, in women, menstrual-cycle or
      menopausal-status stratification), immune (circulating Th17 and regulatory T cell
      frequencies and cytokine profiles), and pain processing (quantitative sensory
      testing with conditioned pain modulation and temporal summation, and skin-biopsy
      intraepidermal nerve fiber density). The first-order result is whether the
      diagnostic criteria themselves ascertain men and women differently.
    experiment_type:
      preferred_term: sex-stratified cross-sectional mechanistic cohort study
    readouts:
    - name: Sex difference in HPA axis reactivity
      target: pathophysiology#HPA Axis Dysregulation
      direction: PRESENT_ABSENT
    - name: Sex difference in inflammatory and T cell profile
      target: pathophysiology#Neuroinflammation
      direction: PRESENT_ABSENT
    - name: Sex difference in central pain amplification
      target: pathophysiology#Central Sensitization
      direction: PRESENT_ABSENT
    controls:
    - name: Sex-matched pain-free controls
      description: >-
        Pain-free men and women matched for age and BMI, so that any observed
        difference is specific to fibromyalgia rather than a normal sex difference
        in the same measure.
    decision_criterion: >-
      The gap resolves toward true biological sex difference if men and women meeting
      identical criteria diverge on one or more mechanistic readouts beyond the sex
      difference seen in controls. It resolves toward ascertainment bias if the
      mechanistic profiles are equivalent once diagnosis is applied symmetrically,
      implying the female predominance is generated at the point of diagnosis.
datasets:
- accession: geo:GSE221921
  title: Identification of unique genomic signatures in patients with fibromyalgia and chronic pain
  description: Fibromyalgia is a chronic pain syndrome characterized by widespread pain. The pathophysiology of fibromyalgia is not clearly understood and there are no specific biomarkers available for accurate diagnosis. Here we define genomic signatures using high throughput RNA sequencing on 96 fibromyalgia and 93 matched controls. Our findings revealed two major fibromyalgia-associated expression signatures. The first group included 44 patients with a signature enriched for gene expression associated with extracellular matrix and downregulation of RhoGDI signaling pathway.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 189
  publication: PMID:38366049
  notes: Identified by GEO DataSets index search for Fibromyalgia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE269047
  title: HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity
  description: Research of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM), two acquired chronic illnesses affecting mainly females, has failed to ascertain their frequent co-appearance and etiology. Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 43
  publication: PMID:40338225
  notes: Identified by GEO DataSets index search for Fibromyalgia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE67311
  title: Peripheral Blood Gene Expression in Fibromyalgia Patients Reveals  Potential Biological Markers and Physiological Pathways
  description: Fibromyalgia (FM) is a common pain disorder characterized by dysregulation in the processing of pain. Although FM has similarities with other rheumatologic pain disorders, the search for objective markers has not been successful. In the current study we analyzed gene expression in the whole blood of 70 fibromyalgia patients and 70 healthy matched controls. Global molecular profiling revealed an upregulation of several inflammatory molecules in FM patients and downregulation of specific pathways related to hypersensitivity and allergy. There was a differential expression of genes in known pathways for pain processing, such as glutamine/glutamate signaling and axonal development.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 142
  publication: PMID:27157394
  notes: Identified by GEO DataSets index search for Fibromyalgia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003825
  title: Exome sequencing of Fibromyalgia patients
  description: Fibromyalgia is a complex disorder characterized by increased sensitivity to pain and extreme tiredness. It affects mostly women, and its causes are unknown. In this study we have performed exome sequencing of 87 fibromyalgia cases, including some sibling pairs, to perform rare variant association analysis and identify fibromyalgia risk factors. A few of the included samples have been also included in a previous GWAS study.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Fibromyalgia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003826
  title: Exome sequencing of Fibromyalgia patients
  description: Fibromyalgia is a complex disorder characterized by increased sensitivity to pain and extreme tiredness. It affects mostly women, and its causes are unknown. In this study we have performed exome sequencing of 87 fibromyalgia cases, including some sibling pairs, to perform rare variant association analysis and identify fibromyalgia risk factors. A few of the included samples have been also included in a previous GWAS study.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Fibromyalgia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001005004
  title: 'Fibromyalgia versus small fiber neuropathy: Diverse keratinocyte transcriptome signature'
  description: We provide a diverse keratinocyte transcriptome signature between SFN and FMS patients, which may hint towards distinct pathomechanisms of small fiber sensitization and lay the basis for advanced diagnostics in both entities
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:33675632
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Fibromyalgia"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: massive:MSV000090685
  title: Proteomic Analysis of Cerebrospinal Fluids from Chronic Fatigue Syndrome Patients with and without Co-existing Fibromyalgia
  description: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other. To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Fibromyalgia"). Retrieved 2026-08-02.
references:
- reference: DOI:10.1097/pr9.0000000000001220
  title: Small fiber pathology in fibromyalgia syndrome
  findings: []
- reference: DOI:10.1101/2024.09.13.24313599
  title: A multi-omics bidirectional mendelian randomization study and
    meta-analysis on the causal relationship between gut microbiota,
    inflammatory proteins, and fibromyalgia.
  findings: []
- reference: DOI:10.1101/2025.09.18.25335914
  title: The genetic architecture of fibromyalgia across 2.5 million individuals
  findings: []
- reference: DOI:10.3390/biomedicines11041119
  title: A Comprehensive Review of the Genetic and Epigenetic Contributions to
    the Development of Fibromyalgia
  findings: []
- reference: DOI:10.3390/biomedicines13020503
  title: 'Fibromyalgia, Depression, and Autoimmune Disorders: An Interconnected Web
    of Inflammation'
  findings: []
- reference: DOI:10.3390/medicina60020272
  title: 'Unraveling the Complex Web of Fibromyalgia: A Narrative Review'
  findings: []
📚

References & Deep Research

References

6
DOI:10.1097/pr9.0000000000001220
Small fiber pathology in fibromyalgia syndrome
No top-level findings curated for this source.
DOI:10.1101/2024.09.13.24313599
A multi-omics bidirectional mendelian randomization study and meta-analysis on the causal relationship between gut microbiota, inflammatory proteins, and fibromyalgia.
No top-level findings curated for this source.
DOI:10.1101/2025.09.18.25335914
The genetic architecture of fibromyalgia across 2.5 million individuals
No top-level findings curated for this source.
DOI:10.3390/biomedicines11041119
A Comprehensive Review of the Genetic and Epigenetic Contributions to the Development of Fibromyalgia
No top-level findings curated for this source.
DOI:10.3390/biomedicines13020503
Fibromyalgia, Depression, and Autoimmune Disorders: An Interconnected Web of Inflammation
No top-level findings curated for this source.
DOI:10.3390/medicina60020272
Unraveling the Complex Web of Fibromyalgia: A Narrative Review
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Fibromyalgia
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 30

Key Pathophysiology Nodes

  • Central Sensitization
  • Descending Pain Modulation Dysfunction
  • Neuroinflammation
  • HPA Axis Dysregulation
  • Small Fiber Pathology
  • Genetic Susceptibility
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1097/pr9.0000000000001220
  • DOI:10.1101/2024.09.13.24313599
  • DOI:10.1101/2025.09.18.25335914
  • DOI:10.3390/biomedicines11041119
  • DOI:10.3390/biomedicines13020503
  • DOI:10.3390/medicina60020272
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 22 citations 2025-12-17T23:36:48.246543

Disease Pathophysiology Research Report

Target Disease - Disease Name: Fibromyalgia (FM) - MONDO ID: (not definitively standardized across sources for FM; commonly referenced in ontologies as a complex, chronic pain syndrome) - Category: Complex

Pathophysiology Description (Narrative) Fibromyalgia is a prototypical nociplastic pain condition characterized by widespread pain, sensory amplification, fatigue, sleep and cognitive symptoms. Contemporary genetic and systems-biology evidence converge on a predominantly central nervous system (CNS) disorder with variable peripheral contributions from small-fiber pathology and immune-inflammation.

Large-scale genetics: A multi-ancestry GWAS meta-analysis across 2.56 million individuals (54,629 cases) identified 26 risk loci and reported that “heritability was exclusively enriched within brain tissues and neural cell types,” implicating neural genes (HTT, GPR52, DRD2/NCAM1, CAMKV, DCC, MDGA2, CELF4) and providing a biological framework that positions FM as a CNS disorder with strong genetic correlations to chronic pain and psychiatric comorbidities (rg > 0.7 with low back pain, PTSD and IBS) (MedRxiv, 2025-09-18; https://doi.org/10.1101/2025.09.18.25335914) (kerrebijn2025thegeneticarchitecture pages 1-2).

Central sensitization, neurotransmitter imbalance and neuroimmune interactions: Clinical and mechanistic reviews emphasize central sensitization driven by maladaptive neuroplasticity (excitatory/inhibitory imbalance involving glutamatergic and GABAergic transmission), altered monoamine signaling (serotonin, norepinephrine, dopamine), and neuroinflammation that sustain pain amplification and multisensory hypersensitivity in FM (Medicina, 2024-02; https://doi.org/10.3390/medicina60020272) (sharie2024unravelingthecomplex pages 4-6). Complementary integrative reviews highlight reduced inhibitory neurotransmission (e.g., decreased insular GABA) and immune-neuroinflammatory signatures (e.g., peripheral cytokines; altered interferon-related proteomics) as recurring findings (Biomedicines, 2023-04; https://doi.org/10.3390/biomedicines11041119) (ovrom2023acomprehensivereview pages 23-25, ovrom2023acomprehensivereview pages 22-23).

Peripheral small-fiber involvement: Approximately half of patients demonstrate small-fiber pathology (SFP) with reduced intraepidermal nerve fiber density (IENFD) and functional C-fiber abnormalities, often in a non–length-dependent or proximal-predominant pattern. A meta-analytic summary indicates about 50% prevalence; one series reported IENFD reduction in 63% of FM patients versus 10% in MDD with pain and 18% in healthy controls. Small-fiber loss correlates with more severe FM and with central MRI changes, supporting a synergy between peripheral input and CNS amplification (Pain Reports, 2025-12; https://doi.org/10.1097/pr9.0000000000001220) (sommer2025smallfiberpathology pages 1-2).

Immune–cytokine and metabolic signatures: Multiple cohorts show elevated pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) in skin or serum correlating with symptom burden, as well as increased IL-17A in some studies. Metabolomic differences include elevated endocannabinoids (anandamide), oleoylethanolamide and palmitoylethanolamide, suggesting altered neuromodulatory tone. Proteomics reveal interferon signatures in B-cells, consistent with immune activation (Biomedicines, 2023-04; https://doi.org/10.3390/biomedicines11041119) (ovrom2023acomprehensivereview pages 14-15). Narrative syntheses further link inflammatory signaling, HPA-axis perturbation and oxidative stress, and highlight experimental data connecting neutrophil-driven neuroinflammation and chronic pain behaviors (Biomedicines, 2025-02; https://doi.org/10.3390/biomedicines13020503) (sedda2025fibromyalgiadepressionand pages 7-8).

Gut–immune axis and causal inference: A multi-omics bidirectional Mendelian randomization preprint identified Ruminococcus gauvreauii as a risk taxon and Enterorhabdus, Parabacteroides, Butyricicoccus, and Prevotella 9 as protective. MR also implicated inflammatory proteins (protective: CXCL5, S100A12, LIFR, CCL8; risk: CD244, IL-12β), supporting a causal role of gut-immune signaling and immune-regulatory pathways in FM (MedRxiv, 2024-09-13; https://doi.org/10.1101/2024.09.13.24313599) (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20).

Key Concepts and Definitions - Nociplastic pain: pain arising from altered nociception without clear tissue or nerve damage, with central sensitization a core mechanism (sharie2024unravelingthecomplex pages 4-6). - Central sensitization: maladaptive neuroplasticity with increased excitability of central nociceptive circuits and impaired descending inhibition; linked to neurotransmitter imbalance (glutamate/GABA; monoamines) and neuroimmune activation (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25). - Small-fiber pathology (SFP): structural and functional abnormalities of thinly myelinated Aδ and unmyelinated C-fibers; in FM often proximal-predominant and present in ~50%, contributing to ongoing peripheral input (sommer2025smallfiberpathology pages 1-2). - Immune-inflammation signature: elevated pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6; sometimes IL-17A), chemokines, and interferon-related proteomics alongside altered lipid mediators (endocannabinoids) (ovrom2023acomprehensivereview pages 14-15).

Recent Developments (2023–2024 priority) - Genetics: CNS-enriched heritability and neural gene prioritization from a multi-ancestry GWAS (2025; methodologically central to current understanding) (kerrebijn2025thegeneticarchitecture pages 1-2). - Gut–immune causal links: MR evidence for specific taxa and cytokine/chemokine proteins affecting FM risk (MedRxiv, 2024-09-13) (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20). - Small-fiber pathology consolidation: Meta-analytic and multimodal evidence reaffirm ~50% prevalence with generalization beyond length-dependent patterns; correlation with FM severity and central changes (Pain Reports, 2025-12) (sommer2025smallfiberpathology pages 1-2). - Integrative immune-neurobiology: Reviews emphasize convergent inflammatory and neuroimmune processes (Biomedicines, 2023-04; 2025-02) (ovrom2023acomprehensivereview pages 23-25, sedda2025fibromyalgiadepressionand pages 7-8).

Current Applications and Real-World Implementations - Diagnostic adjuncts: In suspected SFP, objective measures (IENFD via skin biopsy; corneal confocal microscopy) can document small-fiber loss and support phenotype stratification; recognition that SFP and proximal denervation are common in FM can refine clinical workups and management expectations (sommer2025smallfiberpathology pages 1-2). - Biologically informed management: The CNS-centric architecture (genetics, central sensitization) supports prioritizing centrally acting analgesics and nonpharmacologic neuroplasticity-targeted interventions; immune-metabolic and gut–brain findings motivate lifestyle, anti-inflammatory, and microbiome-modulating strategies in comprehensive care (kerrebijn2025thegeneticarchitecture pages 1-2, ovrom2023acomprehensivereview pages 14-15, niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20).

Expert Opinions and Authoritative Analyses - “Heritability [was] exclusively enriched within brain tissues and neural cell types,” defining FM as a CNS disorder and framing extensive comorbidities via shared genetic liabilities (MedRxiv GWAS, 2025) (kerrebijn2025thegeneticarchitecture pages 1-2). - Narrative and integrative reviews converge on central sensitization with neurotransmitter dysregulation and neuroimmune activation as key sustaining mechanisms, while acknowledging heterogeneity and peripheral contributions (Medicina, 2024; Biomedicines, 2023, 2025) (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25, sedda2025fibromyalgiadepressionand pages 7-8).

Relevant Statistics and Data from Recent Studies - GWAS meta-analysis: N = 2,563,755 (54,629 cases; 2,509,126 controls); 26 loci; rg > 0.7 with low back pain, PTSD, IBS; strongest locus at HTT; neural gene prioritization; CNS heritability enrichment (MedRxiv, 2025) (kerrebijn2025thegeneticarchitecture pages 1-2). - Small-fiber pathology prevalence: ~50% of FM patients with reduced IENFD; in one dataset, 63% of FM vs 10% MDD with pain vs 18% controls; generalized small-fiber loss and proximal predominance reported; functional C-fiber abnormalities on microneurography (Pain Reports, 2025) (sommer2025smallfiberpathology pages 1-2). - Cytokine and proteomic signatures: Upregulated TNF-α, IL-1β, IL-6, sometimes IL-17A with symptom correlations; interferon signatures in B-cells; endocannabinoid and lipid mediator elevations (Biomedicines, 2023) (ovrom2023acomprehensivereview pages 14-15). - Gut–immune MR: Risk taxon Ruminococcus gauvreauii; protective taxa Enterorhabdus, Parabacteroides, Butyricicoccus, Prevotella 9; protective proteins (CXCL5, S100A12, LIFR, CCL8) and risk proteins (CD244, IL-12β) (MedRxiv, 2024) (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20).

Required Information 1) Core Pathophysiology - Primary mechanisms: Central sensitization with excitatory–inhibitory imbalance (glutamate/GABA), altered monoamine signaling (serotonin/norepinephrine/dopamine), neuroimmune activation; variable peripheral small-fiber pathology augmenting nociceptive input (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25, sommer2025smallfiberpathology pages 1-2). - Dysregulated molecular pathways: Neural plasticity and synaptic signaling (HTT, GPR52, DRD2/NCAM1, CAMKV, DCC, MDGA2, CELF4); cytokine/chemokine signaling (IL-6, IL-1β, TNF-α, IL-17A); endocannabinoid and lipid mediator metabolism; interferon-related B-cell programs (kerrebijn2025thegeneticarchitecture pages 1-2, ovrom2023acomprehensivereview pages 14-15). - Affected cellular processes: Synaptic potentiation and disinhibition; microglia/immune-mediated neuroinflammatory signaling; peripheral nociceptor sensitization; stress-response and metabolic signaling changes (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25, ovrom2023acomprehensivereview pages 14-15, sommer2025smallfiberpathology pages 1-2).

2) Key Molecular Players - Genes/Proteins (HGNC examples): HTT, GPR52, DRD2, NCAM1, DCC, CAMKV, MDGA2, CELF4 from GWAS prioritization (kerrebijn2025thegeneticarchitecture pages 1-2). Cytokines: IL6, IL1B, TNF, IL17A (ovrom2023acomprehensivereview pages 14-15). Chemokines: CCL8 (MCP-2), CXCL5, etc. (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20). - Chemical entities (CHEBI): Anandamide (CHEBI:28148), oleoylethanolamide (CHEBI:71464), palmitoylethanolamide (CHEBI:8063) elevated in plasma (ovrom2023acomprehensivereview pages 14-15). - Cell types (CL): Microglia (CL:0000129); peripheral sensory neurons including C-fiber nociceptors (CL:0000099) (sommer2025smallfiberpathology pages 1-2, ovrom2023acomprehensivereview pages 23-25, ovrom2023acomprehensivereview pages 14-15). - Anatomical locations (UBERON): Brain (UBERON:0000955), Skin (UBERON:0002097) with reduced IENFD; proximal patterning reported in FM (kerrebijn2025thegeneticarchitecture pages 1-2, sommer2025smallfiberpathology pages 1-2).

3) Biological Processes (GO annotation) - CNS synaptic signaling and plasticity; glutamatergic signaling; GABAergic inhibitory transmission; dopaminergic modulation (GO: synaptic signaling) (sharie2024unravelingthecomplex pages 4-6, kerrebijn2025thegeneticarchitecture pages 1-2). - Inflammatory response/chemokine-mediated signaling; Th17-related cytokine signaling (IL-17A) (ovrom2023acomprehensivereview pages 14-15, niu2024amultiomicsbidirectional pages 1-5). - Nociception and peripheral nerve degeneration/regeneration processes in small-fiber pathology (sommer2025smallfiberpathology pages 1-2). - Immune-regulatory processes suggested by MR-proteins (e.g., CXCL5, LIFR) (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20).

4) Cellular Components - Synapses and postsynaptic densities (central circuits); inhibitory interneuron networks and descending modulatory pathways (sharie2024unravelingthecomplex pages 4-6, kerrebijn2025thegeneticarchitecture pages 1-2). - Peripheral nerve terminals in epidermis (IENFD) and cornea (CCM) (sommer2025smallfiberpathology pages 1-2). - Microglial and immune cell compartments contributing to neuroinflammation (ovrom2023acomprehensivereview pages 23-25, sedda2025fibromyalgiadepressionand pages 7-8).

5) Disease Progression - Putative sequence: Predisposing CNS-centric genetic architecture (neural gene risk; CNS enrichment) → triggers (stress, infections, injury) → central sensitization with E/I imbalance and impaired descending inhibition → neuroimmune activation (cytokines/chemokines) and variable peripheral SFP sustaining nociceptive input → symptom chronification with multisystem involvement (sleep, mood, cognition, autonomic features) (kerrebijn2025thegeneticarchitecture pages 1-2, sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 14-15, sommer2025smallfiberpathology pages 1-2). - Phases: Initiation (trigger/exacerbation), amplification (central sensitization with peripheral inputs), stabilization/chronification (network-level plasticity and immune-metabolic adaptation) (sharie2024unravelingthecomplex pages 4-6, ovrom2023acomprehensivereview pages 23-25, sommer2025smallfiberpathology pages 1-2).

6) Phenotypic Manifestations - Clinical phenotypes: Widespread pain and hyperalgesia/allodynia; fatigue; non-restorative sleep; cognitive/affective symptoms (nociplastic pattern) (sharie2024unravelingthecomplex pages 4-6). - Mechanistic links: Central sensitization explains sensory amplification; SFP explains neuropathic descriptors and autonomic features; cytokine/immune dysregulation links to sickness behaviors, fatigue, mood alterations; monoaminergic and endocannabinoid changes connect to pain modulation and affect (sommer2025smallfiberpathology pages 1-2, ovrom2023acomprehensivereview pages 14-15, sharie2024unravelingthecomplex pages 4-6).

Gene/Protein Annotations with Ontology Terms, Phenotypes, Cells, Anatomy, Chemicals, Evidence | Entity Type | Name (with ontology ID) | Role / Annotation (GO/HP/CL/UBERON/CHEBI terms as applicable) | Mechanistic Notes | Evidence | |---|---|---|---|---| | Gene / Protein | HTT (HGNC:HTT) | GO: synaptic signaling; CNS development | Coding variant identified as strongest GWAS signal; implicates neural circuitry and CNS contribution to FM risk. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | GPR52 (HGNC:GPR52) | GO: G-protein coupled receptor activity; neuronal signaling | GWAS-prioritized regulator of HTT; suggests GPCR-mediated modulation of neural excitability in FM. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | DRD2 (HGNC:DRD2) / NCAM1 (HGNC:NCAM1) | GO: dopamine signaling; synaptic adhesion | Genetic prioritization implicates dopaminergic and cell-adhesion pathways linked to pain modulation and affective symptoms. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | DCC (HGNC:DCC) | GO: axon guidance; neural development | Risk locus with neural role, consistent with altered CNS connectivity and nociceptive processing. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | CAMKV (HGNC:CAMKV) | GO: synaptic plasticity; calcium/calmodulin-dependent processes | Implicates synaptic plasticity mechanisms (central sensitization) in FM pathophysiology. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | MDGA2 (HGNC:MDGA2) | GO: neuronal migration; synapse organization | Neural development/synapse gene prioritized by GWAS, supporting CNS-centric disease architecture. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Gene / Protein | CELF4 (HGNC:CELF4) | GO: RNA binding; regulation of neuronal excitability | Neuronally expressed RNA-binding protein implicated by genetics; may affect expression of excitability-related transcripts. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Cytokine / Immune | IL6 (Interleukin-6) | GO: inflammatory response; HP: increased circulating IL-6 | Frequently reported elevated in FM cohorts; correlates with pain severity and disability in multiple studies. | (ovrom2023acomprehensivereview pages 14-15) | | Cytokine / Immune | CXCL8 / IL8 (CHEBI:IL8) | GO: chemokine-mediated signaling; neutrophil chemotaxis | Part of peripheral cytokine signature distinguishing FM from controls; associated with pain and tissue fat infiltration indices. | (ovrom2023acomprehensivereview pages 14-15) | | Cytokine / Immune | TNF / TNF-alpha | GO: pro-inflammatory cytokine activity | Elevated in some FM cohorts; implicated in systemic low-grade inflammation that may amplify central sensitization. | (ovrom2023acomprehensivereview pages 14-15) | | Cytokine / Immune | IL17A (Interleukin-17A) | GO: cytokine-mediated signaling pathway; Th17 responses | Reported increased in skin/serum in FM; links to immune-driven peripheral sensitization and comorbid autoimmune signals. | (ovrom2023acomprehensivereview pages 14-15) | | Cell type | Nociceptor C-fibers (CL:0000099) | CL: peripheral sensory neuron; GO: nociception | Structural/functional small-fibre pathology (reduced IENFD, altered microneurography) present in ~50% of FM cohorts, contributing peripheral nociceptive input. | (sommer2025smallfiberpathology pages 1-2) | | Cell type | Microglia (CL:0000129) | CL: microglial cell; GO: neuroinflammatory response | Microglial activation / neuroinflammation proposed to sustain central sensitization and pain amplification in FM. | (ovrom2023acomprehensivereview pages 14-15) | | Anatomical location | Skin (UBERON:0002097) | UBERON: skin; GO: peripheral nerve innervation | Reduced intraepidermal nerve fibre density (IENFD) and proximal patterning reported in ~50% of FM patients; supports peripheral contribution to symptoms. | (sommer2025smallfiberpathology pages 1-2) | | Anatomical location | Brain (UBERON:0000955) | UBERON: brain; GO: central nervous system development | GWAS tissue-enrichment and imaging implicate brain tissues and neural cell types as primary sites of genetic risk and altered function in FM. | (kerrebijn2025thegeneticarchitecture pages 1-2) | | Chemical / Metabolite | Anandamide (CHEBI:28148) | CHEBI: endocannabinoid; GO: modulation of synaptic transmission | Elevated endocannabinoid (anandamide) and related lipids reported in plasma metabolomics, suggesting altered neuromodulatory tone in FM. | (ovrom2023acomprehensivereview pages 14-15) |

Table: A compact, ontology-linked table summarizing genes, immune mediators, cell types, anatomical sites, and a key metabolite implicated in fibromyalgia pathophysiology, with concise mechanistic notes and primary evidence citations for knowledge-base use.

Evidence Items (PMIDs/DOIs/URLs and dates) - GWAS CNS enrichment and neural loci: Kerrebijn I et al. MedRxiv. 2025-09-18. https://doi.org/10.1101/2025.09.18.25335914 (kerrebijn2025thegeneticarchitecture pages 1-2) - Central sensitization and neurotransmitter dysregulation: Sharie SA et al. Medicina. 2024-02. https://doi.org/10.3390/medicina60020272 (sharie2024unravelingthecomplex pages 4-6) - Integrative genetic/epigenetic and immune-neurochemical evidence: Ovrom EA et al. Biomedicines. 2023-04. https://doi.org/10.3390/biomedicines11041119 (ovrom2023acomprehensivereview pages 23-25, ovrom2023acomprehensivereview pages 22-23, ovrom2023acomprehensivereview pages 14-15) - Small-fiber pathology prevalence and characteristics: Sommer C, Üçeyler N. Pain Reports. 2025-12. https://doi.org/10.1097/pr9.0000000000001220 (sommer2025smallfiberpathology pages 1-2) - Gut–immune MR links (taxa, cytokines/chemokines): Niu M et al. MedRxiv. 2024-09-13. https://doi.org/10.1101/2024.09.13.24313599 (niu2024amultiomicsbidirectional pages 1-5, niu2024amultiomicsbidirectional pages 16-20) - Immune–neuroinflammation in FM, depression and autoimmune disorders: Sedda S et al. Biomedicines. 2025-02. https://doi.org/10.3390/biomedicines13020503 (sedda2025fibromyalgiadepressionand pages 7-8)

Notes and Limitations - Some mechanistic domains remain under active investigation. For example, human neuroinflammation imaging (e.g., TSPO-PET) and specific biomarker panels (e.g., BDNF) are promising but require further replication and standardization; the present report prioritizes sources retrieved and directly evidenced in this synthesis (ovrom2023acomprehensivereview pages 23-25, sharie2024unravelingthecomplex pages 4-6, kerrebijn2025thegeneticarchitecture pages 1-2).

References

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