Hypermobile Ehlers-Danlos Syndrome <-> Fibromyalgia

Comorbidity UNKNOWN CANDIDATE

Well-documented comorbidity: a large propensity-matched cohort (59,128 matched pairs) found fibromyalgia in 9.5% of hEDS/EDS patients versus matched controls (OR 1.7). A dedicated systematic review of concomitant diagnosis found an even higher clinical overlap (68%-88.9% of hEDS/HSD patients also carry a fibromyalgia diagnosis), reflecting shared diagnostic features (widespread pain, tenderness, fatigue) as much as a true co-occurrence rate. Directionality is UNKNOWN -- both are typically lifelong/chronic conditions without an established temporal precedence. No ICEES KG signal exists for this pair: hEDS (MONDO:0007523) is not a node in the ICEES KG snapshot at all (confirmed while curating the hEDS-POTS comorbidity entry), so no ICEES-sourced signal is possible for any hEDS pair in the current snapshot.

Disease A

Hypermobile Ehlers-Danlos Syndrome

Slug:Hypermobile_Ehlers-Danlos_Syndrome

Disease B

Fibromyalgia

Slug:Fibromyalgia

Causal Mechanism Graphs

Hypermobile Ehlers-Danlos Syndrome

graph LR
    Joint_instability_and_recurrent_soft_tissue_injury["Joint instability and recurrent soft-tissue injury"]
    Joint_dislocation["Joint dislocation"]
    Candidate_extracellular_matrix_remodeling_abnormalities["Candidate extracellular matrix remodeling abnormalities"]
    Sleep_disturbance["Sleep disturbance"]
    Chronic_pain["Chronic pain"]
    Arthralgia["Arthralgia"]
    Joint_hypermobility["Joint hypermobility"]
    Myofibroblast_like_fibroblast_transition["Myofibroblast-like fibroblast transition"]

    Candidate_extracellular_matrix_remodeling_abnormalities --> Myofibroblast_like_fibroblast_transition
    Joint_instability_and_recurrent_soft_tissue_injury --> Joint_dislocation
    Joint_instability_and_recurrent_soft_tissue_injury --> Chronic_pain
    Joint_instability_and_recurrent_soft_tissue_injury --> Arthralgia
    Joint_hypermobility --> Joint_instability_and_recurrent_soft_tissue_injury
    Chronic_pain --> Sleep_disturbance

    style Joint_instability_and_recurrent_soft_tissue_injury fill:#dbeafe
    style Joint_dislocation fill:#fef3c7
    style Candidate_extracellular_matrix_remodeling_abnormalities fill:#dbeafe
    style Sleep_disturbance fill:#fef3c7
    style Chronic_pain fill:#fef3c7
    style Arthralgia fill:#fef3c7
    style Joint_hypermobility fill:#fef3c7
    style Myofibroblast_like_fibroblast_transition fill:#dbeafe

Fibromyalgia

graph LR
    Central_Sensitization["Central Sensitization"]
    Small_Fiber_Pathology["Small Fiber Pathology"]
    Neuroinflammation["Neuroinflammation"]

    Neuroinflammation --> Central_Sensitization
    Small_Fiber_Pathology --> Central_Sensitization

    style Central_Sensitization fill:#dbeafe
    style Small_Fiber_Pathology fill:#dbeafe
    style Neuroinflammation fill:#dbeafe

Association Signals

Signal 1

Population:TriNetX research network, retrospective propensity-matched analysis (2005-2023), 59,128 matched pairs of EDS patients (excluding Marfan syndrome) versus controls.

Signal IDs: MONDO:0007523 dismech -> MONDO:0005546 dismech

Temporal: A before B: , B before A: , Same time:

PREVALENCE: 9.5

CI: -

FDR:

Fibromyalgia prevalence in the EDS cohort.

OR: 1.7

CI: 1.6 - 1.8

p: 0.001

FDR:

Odds ratio for fibromyalgia in EDS versus propensity-matched controls. Reported by the source as p < 0.001, an upper bound, not a point estimate.

PMID:41432355 (SUPPORT)

Source: HUMAN_CLINICAL

"Systemic comorbidities included postural orthostatic tachycardia syndrome (13.2%, OR 899.7, 95% CI 483.8-1673.0, p < 0.001), chronic pain (7.9%, OR 7.0, 95% CI 6.4-7.6, p < 0.001), migraines (19.7%, OR 2.5, 95% CI 2.4-2.6, p < 0.001) and fibromyalgia (9.5%, OR 1.7, 95% CI 1.6-1.8, p < 0.001)."

A large propensity-matched cohort quantifies elevated fibromyalgia prevalence and odds ratio in EDS patients.

Signal 2

Population:Systematic review of 11 observational studies (9 case-control, 2 single group) of adults screened for hEDS/HSD/generalized joint hypermobility and fibromyalgia.

Signal IDs: MONDO:0007523 dismech -> MONDO:0005546 dismech

Mapping notes:This concomitant-diagnosis prevalence range (68%-88.9%) is much higher than the population-level OR from the large TriNetX cohort above, likely reflecting selection into specialty hEDS/HSD clinics and diagnostic feature overlap between the two conditions rather than a directly comparable population-level co-occurrence rate. Both figures are recorded rather than reconciled into one number.

Temporal: A before B: , B before A: , Same time:

PREVALENCE: 88.9

CI: -

FDR:

Upper bound of the reported concomitant-diagnosis prevalence range (68%-88.9%) across the reviewed studies.

PMID:36462303 (SUPPORT)

Source: HUMAN_CLINICAL

"The prevalence of concomitant diagnosis of hEDS/HSD and FMS ranged from 68%-88.9% and from 8.0 to 64.2% for GJH and FMS."

Systematic review of concomitant-diagnosis prevalence in specialty-clinic hEDS/HSD populations.

Hypotheses

Hypothesis: connective-tissue laxity in hEDS alters mechanoreceptor and nociceptor signaling from joints, fascia, and skin, contributing to peripheral sensitization; over time this drives central sensitization of pain-processing pathways, producing the widespread pain and tenderness that defines fibromyalgia. A broader meta-analysis of "functional somatic syndromes" (pooling fibromyalgia, chronic fatigue syndrome, and functional GI disorders) found a significantly elevated odds of joint hypermobility across this syndrome cluster, consistent with a shared predisposition rather than fibromyalgia being a distinct, unrelated diagnosis.

PMID:34237584 (SUPPORT)

Source: HUMAN_CLINICAL

"Meta-analysis showed a weighted summary effect odds ratio of 3.27 (95% CI: 1.83, 5.84; p < 0.001) of JH in FSS, suggesting greater odds of FSS in individuals with JH than in those without."

A meta-analysis of 10 controlled studies (5 on fibromyalgia specifically) finds significantly elevated joint hypermobility in functional somatic syndromes including fibromyalgia, consistent with a shared predisposition.

PMID:36462303 (SUPPORT)

Source: HUMAN_CLINICAL

"The prevalence and severity of a range of objective and patient-reported features were similar between hEDS/HSD and FMS, including joint pain (duration, persistence, SF-36-pain component score); joint swelling; muscle weakness; neurological problems; multidimensional pain inventory-activity; dysautonomia and total autonomic symptoms burden"

Documents extensive symptomatic overlap between hEDS/HSD and fibromyalgia beyond diagnostic co-occurrence alone, supporting a shared underlying pain/sensitization mechanism rather than coincidental comorbidity.

Pathophysiology:

Central pain sensitization: Chronic nociceptive input from unstable, hypermobile joints and lax connective tissue is proposed to drive central sensitization of pain processing, producing the widespread pain and tenderness of fibromyalgia.

Biological processes:

Raw YAML

Show YAML

name: com_Hypermobile_Ehlers-Danlos_Syndrome__Fibromyalgia
creation_date: '2026-09-18T02:40:05Z'
curation_status: CANDIDATE
notes: >-
  Well-documented comorbidity: a large propensity-matched cohort (59,128
  matched pairs) found fibromyalgia in 9.5% of hEDS/EDS patients versus
  matched controls (OR 1.7). A dedicated systematic review of concomitant
  diagnosis found an even higher clinical overlap (68%-88.9% of hEDS/HSD
  patients also carry a fibromyalgia diagnosis), reflecting shared diagnostic
  features (widespread pain, tenderness, fatigue) as much as a true
  co-occurrence rate. Directionality is UNKNOWN -- both are typically
  lifelong/chronic conditions without an established temporal precedence. No
  ICEES KG signal exists for this pair: hEDS (MONDO:0007523) is not a node in
  the ICEES KG snapshot at all (confirmed while curating the hEDS-POTS
  comorbidity entry), so no ICEES-sourced signal is possible for any hEDS
  pair in the current snapshot.

disease_a:
  slug: Hypermobile_Ehlers-Danlos_Syndrome
  preferred_term: Ehlers-Danlos syndrome, hypermobility type
  term:
    id: MONDO:0007523
    label: Ehlers-Danlos syndrome, hypermobility type

disease_b:
  slug: Fibromyalgia
  preferred_term: fibromyalgia
  term:
    id: MONDO:0005546
    label: fibromyalgia

directionality: UNKNOWN

hypotheses:
- description: >-
    Hypothesis: connective-tissue laxity in hEDS alters mechanoreceptor and
    nociceptor signaling from joints, fascia, and skin, contributing to
    peripheral sensitization; over time this drives central sensitization of
    pain-processing pathways, producing the widespread pain and tenderness
    that defines fibromyalgia. A broader meta-analysis of "functional somatic
    syndromes" (pooling fibromyalgia, chronic fatigue syndrome, and
    functional GI disorders) found a significantly elevated odds of joint
    hypermobility across this syndrome cluster, consistent with a shared
    predisposition rather than fibromyalgia being a distinct, unrelated
    diagnosis.
  evidence:
  - reference: PMID:34237584
    reference_title: "Functional somatic syndromes and joint hypermobility: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meta-analysis showed a weighted summary effect odds ratio of 3.27 (95% CI: 1.83, 5.84; p < 0.001) of JH in FSS, suggesting greater odds of FSS in individuals with JH than in those without."
    explanation: >-
      A meta-analysis of 10 controlled studies (5 on fibromyalgia
      specifically) finds significantly elevated joint hypermobility in
      functional somatic syndromes including fibromyalgia, consistent with a
      shared predisposition.
  - reference: PMID:36462303
    reference_title: "The concomitant diagnosis of fibromyalgia and connective tissue disorders: A systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence and severity of a range of objective and patient-reported features were similar between hEDS/HSD and FMS, including joint pain (duration, persistence, SF-36-pain component score); joint swelling; muscle weakness; neurological problems; multidimensional pain inventory-activity; dysautonomia and total autonomic symptoms burden"
    explanation: >-
      Documents extensive symptomatic overlap between hEDS/HSD and
      fibromyalgia beyond diagnostic co-occurrence alone, supporting a shared
      underlying pain/sensitization mechanism rather than coincidental
      comorbidity.
  pathophysiology:
  - name: Central pain sensitization
    description: >-
      Chronic nociceptive input from unstable, hypermobile joints and lax
      connective tissue is proposed to drive central sensitization of pain
      processing, producing the widespread pain and tenderness of
      fibromyalgia.
    biological_processes:
    - preferred_term: sensory perception of pain
      term:
        id: GO:0019233
        label: sensory perception of pain

association_signals:
- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005546
  population: >-
    TriNetX research network, retrospective propensity-matched analysis
    (2005-2023), 59,128 matched pairs of EDS patients (excluding Marfan
    syndrome) versus controls.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: PREVALENCE
      metric_value: 9.5
      notes: Fibromyalgia prevalence in the EDS cohort.
    - metric_type: OR
      metric_value: 1.7
      metric_ci_lower: 1.6
      metric_ci_upper: 1.8
      p_value: 0.001
      notes: Odds ratio for fibromyalgia in EDS versus propensity-matched controls. Reported by the source as p < 0.001, an upper bound, not a point estimate.
    evidence:
    - reference: PMID:41432355
      reference_title: "Comprehensive Risk Profile of Gastrointestinal and Extra Articular Comorbidities in Ehlers-Danlos Syndrome: A Propensity-Matched Analysis of 118,256 Individuals."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Systemic comorbidities included postural orthostatic tachycardia syndrome (13.2%, OR 899.7, 95% CI 483.8-1673.0, p < 0.001), chronic pain (7.9%, OR 7.0, 95% CI 6.4-7.6, p < 0.001), migraines (19.7%, OR 2.5, 95% CI 2.4-2.6, p < 0.001) and fibromyalgia (9.5%, OR 1.7, 95% CI 1.6-1.8, p < 0.001)."
      explanation: A large propensity-matched cohort quantifies elevated fibromyalgia prevalence and odds ratio in EDS patients.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005546
  population: >-
    Systematic review of 11 observational studies (9 case-control, 2 single
    group) of adults screened for hEDS/HSD/generalized joint hypermobility
    and fibromyalgia.
  mapping_notes: >-
    This concomitant-diagnosis prevalence range (68%-88.9%) is much higher
    than the population-level OR from the large TriNetX cohort above, likely
    reflecting selection into specialty hEDS/HSD clinics and diagnostic
    feature overlap between the two conditions rather than a directly
    comparable population-level co-occurrence rate. Both figures are recorded
    rather than reconciled into one number.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: PREVALENCE
      metric_value: 88.9
      notes: >-
        Upper bound of the reported concomitant-diagnosis prevalence range
        (68%-88.9%) across the reviewed studies.
    evidence:
    - reference: PMID:36462303
      reference_title: "The concomitant diagnosis of fibromyalgia and connective tissue disorders: A systematic review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The prevalence of concomitant diagnosis of hEDS/HSD and FMS ranged from 68%-88.9% and from 8.0 to 64.2% for GJH and FMS."
      explanation: Systematic review of concomitant-diagnosis prevalence in specialty-clinic hEDS/HSD populations.

Source:GitHub